With Trump no longer in the White House, stories examining the hypothesis that SARS-CoV-2 originated in the Wuhan Virology lab exploded in May.

See the National Security Evidence File for our take on the most important consequences of this new development.

The race between the spread of B.1.617.2 (the Indian or Delta variance) and vaccination rates and efficacy accelerated in May.

With cases of the B.1.617.2 variant rapidly displacing B.117 in the UK, it is clear that the latter’s estimated 50% transmissibility advantage over the former means that it is on course to become the world’s dominant strain of SARS-CoV-2, at least until an even more transmissible mutation or recombination appears.

As we have written before, there are two pieces of good news: Vaccine efficacy against the new variant appears to be quite strong, and thus far relatively limited evidence suggests that it is unlikely to make people sicker than previous variants.

It thus appears that the speed of vaccination and percent of the population that is fully vaccinated are the keys to avoiding stress on national medical systems and thus the need for further lockdowns and other behavioral interventions with all the mental health, student learning losses and other social, economic, and political costs they bring with them.

Unfortunately these still vary widely around the world, leading to the conclusion that SARS-CoV-2 still has the potential to cause substantial further damage to at least some parts of the global political economy.

As Brilliant and his co-authors note in “The Forever Virus”, “It is time to say it out loud: the virus behind the COVID-19 pandemic is not going away. SARS-CoV-2 cannot be eradicated, since it is already growing in more than a dozen different animal species.

“Among humans, global herd immunity, once promoted as a singular solution, is unreachable. Most countries simply don’t have enough vaccines to go around, and even in the lucky few with an ample supply, too many people are refusing to get the shot. As a result, the world will not reach the point where enough people are immune to stop the virus’s spread before the emergence of dangerous variants—ones that are more transmissible, vaccine resistant, and even able to evade current diagnostic tests. Such supervariants could bring the world back to square one. It might be 2020 all over again.

“Rather than die out, the virus will likely ping-pong back and forth across the globe for years to come.”

“Origin of COVID — Following the Clues”, by Richard Wade

https://nicholaswade.medium.com/origin-of-covid-following-the-clues-6f03564c038

SURPRISE

This is by far the most thorough investigation of the origins of the SARS-CoV-2 virus that I have seen to date.
Wade is a highly respected science journalist, and this is a must read.

He concludes: “If the case that SARS2 originated in a lab is so substantial, why isn’t this more widely known? As may now be obvious, there are many people who have reason not to talk about it…

“To these serried walls of silence must be added that of the mainstream media. To my knowledge, no major newspaper or television network has yet provided readers with an in-depth news story of the lab escape scenario, such as the one you have just read…People round the world who have been pretty much confined to their homes for the last year might like a better answer than their media are giving them.”

Two critical question are (1) How the accumulating evidence regarding the origins of the COVID pandemic will affect other nations’ attitudes toward China (it’s pretty certain they will harden), and

(2) How this will affect Xi’s decisions – e.g., with respect to Taiwan and conflict with the United States. Will harder attitudes on the part of other nations constrain Xi, or make him think he has nothing to lose risking war with the US over Taiwan?

April saw the release of a number of studies examining the B.1.617 variant currently spreading in India, as well as the extent of protection provided by current vaccines against other new SARS-CoV-2 variants.

The Bad News: Three preliminary studies confirm that the B.1.607 variant now spreading through India is something to worry about.

In “Convergent Evolution Of SARS-Cov-2 Spike Mutations, L452R, E484Q And P681R, In The Second Wave Of COVID-19 In Maharashtra, India”, Cherian et al provide evidence that B.1.617 is more transmissible than the original Wuhan strain.

In “SARS-Cov-2 Variant B.1.617 Is Resistant To Bamlanivimab And Evades Antibodies Induced By Infection And Vaccination”, Hoffman et al find that, like the B.1.351 South African and P.1 Brazilian variants, B.1.617 has increased ability to evade the antibodies produced by current vaccines. It bears emphasizing that this represents reduced, by not eliminated vaccine efficacy against these strains.

Finally, and most concerning is a third paper, “SARS Cov-2 Variant B.1.617.1 Is Highly Pathogenic In Hamsters Than B.1 Variant”, by Yadav et al. They find that the B.1.617 variant produced more lung lesions and hemorrhages than the original Wuhan strain, which indicates it can cause more serious disease.

The Good News: So far, there is no strong evidence that vaccination provides substantially weaker protection against infection by any of the other SARS-CoV-2 variants of concern.

Also, if you’ve previously had COVID, just your first vaccine dose has a strong effect. However, if you haven’t previously had COVID, you need both doses.

For example, in “Prior SARS-Cov-2 Infection Rescues B And T Cell Responses To Variants After First Vaccine Dose”, Reynolds et al “investigated if single dose vaccination, with or without prior [COVID] infection, confers cross protective immunity to variants… After one dose, individuals with prior infection showed enhanced T cell immunity, antibody secreting memory B cell response to spike and neutralizing antibodies effective against B.1.1.7 [UK variant] and B.1.351 [South African variant].
“By comparison, receiving one vaccine dose without prior infection showed reduced immunity against variants. B.1.1.7 and B.1.351.”

COVID appears to be out of control in India and Brazil.

It remains to be seen what the impact will be on their economies, political stability, and relationships with other countries. Given India’s importance to the emerging Quad alliance (between India, Japan, Australia, and the United States) to contain China, this is a critical uncertainty to monitor.

“Researchers Are Closing In On Long Covid”, in The Economist

SURPRISE

“A wave of what has become known as ‘long COVID’ is emerging in countries where acute cases have been falling. Formally, the condition is called ‘post-COVID syndrome’ (PCS). But even the official definition of its symptoms is fluid, because knowledge of its details is still evolving…

“A sufferer typically has several symptoms at a time, with the most debilitating usually being one of three: severe breathlessness, fatigue or ‘brain fog’…

“Doctors are focusing on three possible biological explanations. One is that long COVID is a persistent viral infection. A second is that it is an autoimmune disorder. The third is that it is a consequence of tissue damage caused by inflammation during the initial, acute infection…

“Britain’s Office for National Statistics (ONS) estimates that 14% of people who have tested positive for covid-19 have symptoms which subsequently linger for more than three months. In more than 90% of those cases the original symptoms were not severe enough to warrant admission to hospital…

“Multiply that by the hundreds of millions around the world who have been infected at some point by SARS-CoV-2 , the virus that causes COVID, and a public-health catastrophe may be in the making.”

The 27Mar21 CDC report on the proportions of difference SARS-CoV-2 variants comprising newly reported infections showed that so-called “variants of concern” (VOC) now account for 65% of COVID infections in the US.”

SURPRISE

The major distinguishing feature of these VOCs is that they are more easily transmitted than the original SARS-CoV-2 strains, because their spike proteins bind more efficiently to human tissue. Hence, infection can result from exposure to a smaller quantity of viral particles.

VOCs include variants first identified in the UK (B.1.1.7), South Africa (B.1.351), Brazil (B.1.1.248 or “P.1”), California (B.1.427 and 429), Nigeria (B.1.525), New York (B.1.526), and India (B.1.617).

A secondary concern with some of the variants (especially the South African, Brazilian, and perhaps Indian strains) is that they have increased resistance to antibodies (and perhaps the T-Cell response) produced either by previous COVID infection or vaccine. However, research has found that vaccines produce substantially more protection than infection with an earlier strain of the virus.

The emergence and evolution of SARS-CoV-2 variants has led vaccine producers to prepare for the production of booster shots targeted at the emerging variants, as is the case today with the annual influenza vaccine.

The critical uncertainties here are threefold:

(1) The rate at which the SARS-CoV-2 virus evolves (via mutation and recombination). Vaccination should slow this; however, the rate of vaccination and the percent of the population that has been vaccinated both vary widely around the world.

(2) The extent to which newly emerging variants of the SARS-CoV-2 virus will be able to evade the protection provided by previous infection and/or vaccination;

(3) The future relationship between the time required for new vaccine development, production, and distribution and the rate at which dangerous new virus variants emerge and spread.

Different outcomes for these uncertainties lead to a range of scenarios, from optimistic (high virus suppression and strong economic recovery) to pessimistic (low virus suppression and weak economic recovery).

See also: “Emerging SARS-CoV-2 Variants and Impact in Global Vaccination Programs against SARS-CoV-2/COVID-19” by Gomez et al

In Canada, infections with the Brazilian P.1 variant are rapidly spreading beyond the original infection site at the Whistler ski resort in British Columbia.

Recent research has found the P.1 is 1.7 to 2.4 times as infectious as the original Wuhan strain of the SARS-CoV-2 virus.

See: “Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil”, by Faria et al, and “Model-Based Estimation Of Transmissibility And Reinfection Of SARS-Cov-2 P.1 Variant”, by Coutinho et al.

SURPRISE

If Canada fails to suppress the emerging P.1 variant outbreak and allows it to rage across the country, the negative impact on market and economic confidence will very likely be substantial.

After extended negotiations with China the preceded its investigation team’s visit to Wuhan, the WHO published its report on the origin of the SARS-CoV-2 virus, which minimized the “lab leak” theory. The report drew a storm of criticism.

For example, see:

“The Scientists Who Say The Lab-Leak Hypothesis For SARS-Cov-2 Shouldn't Be Ruled Out” in the MIT Technology Review

“Theory That COVID Came From A Chinese Lab Takes On New Life In Wake Of WHO Report” on NPR Radio

“An Avalanche of Misdirection”, by Tim Raub in City Journal

“A Joint WHO-China Study Of Covid-19’sorigins Leaves Much Unclear” in The Economist

In two previous reports, Professor Limeng Yan, formerly of the University of Hong Kong, has presented evidence that SARS-CoV-2 originated in and escaped from the Wuhan Virology Laboratory.

In March, she and her team published their third report, which not only provided evidence calling into question previous attempts to discredit the first two reports, but also evidence supporting Yan’s contention that SARS-CoV-2 was created as part of a Chinese biological warfare program (which does contradict the lab escape hypothesis).

She noted this passage from a 2015 book by a group of CCP’s military virologists/scientists headed by professor and Major General Dezhong Xu “that described an ideal ‘contemporary genetic weapon’. The key features of it include:

“It would be created in a way that it is practically indistinguishable from a naturally occurring pathogen. This way, “even if scientific, virological, and/or animal evidence were in place (to support the accusation), (one can) deny, prevent, and suppress the accusation of bioweapon usage, rendering international organizations and the justice side helpless and unable to make the conviction”.

“Its use is not restricted for military battles, but is for non-military settings where it would be ‘causing terror (in) and gaining political and strategic advantage, regionally or internationally, (over the enemy state)’.”

Clearly, there is a potentially very strong feedback loop here between the results of continuing investigation of the origins of SARS-CoV-2 and the rapidly worsening relationship between China and the United States.

More evidence has been published on the effects of “Long COVID”.

In “Post-Covid Syndrome In Individuals Admitted To Hospital With Covid-19: Retrospective Cohort Study”, Ayoubkhani et al report on the results of a follow up study of previously hospitalized COVID patients.

“Over a mean follow-up of 140 days, nearly a third of individuals who were discharged from hospital after acute covid-19 were readmitted (14,060 of 47,780) and more than 1 in 10 (5,875) died after discharge, with these events occurring at rates four and eight times greater, respectively, than in the matched control group. Rates of respiratory disease, diabetes, and cardiovascular disease were also significantly raised in patients with COVID-19.”

In “6-Month Neurological And Psychiatric Outcomes In 236 379 Survivors Of COVID-19: A Retrospective Cohort Study”, Taquet et al found that, “Among 236,379 patients diagnosed with COVID-19, the estimated incidence of a neurological or psychiatric diagnosis in the following 6 months was 34% with 13% (receiving their first such diagnosis.”

“Increased Hazard Of Death In Community-Tested Cases Of 4 SARS-Cov-2 Variant Of Concern 202012/01”, by Davies et al

“Risk Of Mortality In Patients Infected With SARS-Cov-2 Variant Of Concern 202012/1: Matched Cohort Study”, by Challen et al

SURPRISE

The first paper concludes that the B.1.1.7 variant of SARS-CoV-2 that has become dominant in the UK is not only more transmissible, but also increases the risk of dying from COVID (if you’re infected) by about 50%.

To put that in perspective, “this corresponds to the absolute risk of death for a male aged 55–69 increasing from 0.6% to 0.9% over the 28 days following a positive [COVID] test.”

In the second paper, Callen et al found a 64% higHer risk of death if a person is infected, or “an increase in deaths from 2.5 to 4.1 per 1000 detected cases.”

“Negligible Impact Of SARS-Cov-2 Variants On CD4+ And CD8+ T Cell Reactivity In COVID-19 Exposed Donors And Vaccinees” by Tarkle et al

The emergence of SARS-CoV-2 variants highlighted the need to better understand adaptive immune responses to this virus. It is important to address whether also CD4+ and CD8+ T cell responses are affected, because of the role they play in disease resolution and modulation of COVID-19 disease severity…

“We performed a comprehensive analysis of SARS-CoV-2-specific CD4+ and CD8+ T cell responses from COVID-19 convalescent subjects recognizing the ancestral strain, compared to variant lineages B.1.1.7, B.1.351, P.1, and CAL.20C as well as recipients of the Moderna (mRNA-1273) or Pfizer/BioNTech (BNT162b2) COVID-19 vaccines.

“We demonstrate that the sequences of the vast majority of SARS-CoV-2 T cell epitopes are not affected by the mutations found in the variants analyzed. Overall, the results demonstrate that CD4+ and CD8+ T cell responses in convalescent COVID-19 subjects or COVID-19 mRNA vaccinees are not substantially affected by mutations found in the SARS-CoV-2 variants.”

“Modeling And Prediction Of COVID-19 In The United States Considering Population Behavior And Vaccination”, by Usherwood et al

SURPRISE

This innovative analysis models the impact of interacting vaccination rates and behavioral changes of future COVID infections.

However, it does not appear that the authors have factored in the potential impact of the spread of more transmissible SARS-CoV-2 variants in the United States, which would likely extend their forecast for minimal COVID infections beyond August 2021.

“COVID-19 has devastated the entire global community. Vaccines present an opportunity to mitigate the pandemic; however, the effect of vaccination coupled with the behavioral response of the population is not well understood.

“We propose a model that incorporates two important dynamically varying population behaviors: level of caution and sense of safety. Level of caution increases with the number of infectious cases, while an increasing sense of safety with increased vaccination lowers precautionary behaviors.

“To the best of our knowledge, this is the first modeling approach that can effectively reproduce the complete time history of COVID-19 infections for various regions of the United States and provides relatable measures of dynamic changes in the population behavior and disease transmission rates…

“We predict future COVID-19 pandemic trends in the United States accounting for vaccine rollout and behavioral response.

“Although a high rate of vaccination is critical to quickly end the pandemic, we find that a return towards pre-pandemic social behavior due to increased sense of safety during vaccine deployment, can cause an alarming surge in infections.

“Our results indicate that at the current rate of vaccination, the new infection cases for COVID-19 in the United States will approach zero by the end of August 2021.”

“In 2018, Diplomats Warned of Risky Coronavirus Experiments in a Wuhan Lab. No One Listened”, by Josh Rogin in Politico

This is another in-depth analysis of the evidence surrounding the theory that the COVID pandemic was caused by a lab accident at the Wuhan Institute of Virology.

“Bidirectional Associations Between COVID-19 And Psychiatric Disorder: Retrospective Cohort Studies Of 62,354 COVID-19 Cases In The USA”, by Taquet et al

SURPRISE

“Adverse mental health consequences of COVID-19, including anxiety and depression, have been widely predicted but not yet accurately measured.”

The authors find that, “The incidence of any clinical psychiatric diagnosis in the 14 to 90 days after COVID-19 diagnosis was 18⋅1% (95% Confidence interval 17⋅6–18⋅6), including 5⋅8% (5⋅2–6⋅4) that were a first diagnosis.”

“Mental Health, Substance Use, and Suicidal Ideation During the COVID-19 Pandemic — United States, June 24–30, 2020”, by Czeisler et al from the US CD

This study describes the self-reported results of a panel study conducted among 5,412 adults. Unlike the study noted above, these results are not based on clinical diagnoses.

“Overall, 40.9% of respondents reported at least one adverse mental or behavioral health condition, including symptoms of anxiety disorder or depressive disorder (30.9%), symptoms of a trauma- and stressor-related disorder (TSRD) related to the pandemic† (26.3%), and having started or increased substance use to cope with stress or emotions related to COVID-19 (13.3%).

“The percentage of respondents who reported having seriously considered suicide in the 30 days before completing the survey (10.7%) was significantly higher among respondents aged 18–24 years (25.5%), minority racial/ethnic groups (Hispanic respondents [18.6%], non-Hispanic black [black] respondents [15.1%]), self-reported unpaid caregivers for adults (30.7%), and essential workers (21.7%).”

As we predicted in our September 2020 feature article (“An Assessment of Covid-19 Vaccine Uncertainties and Probabilities”), the roll out of vaccines production and distribution across countries has been uneven, but was gradually improving last month.

The key uncertainty at this point is whether and when the continuing evolution of the SARS-CoV-2 virus (i.e., the emergence of more infectious new variants, such as those seen in the UK, South Africa, and Brazil) will sufficiently reduce the efficacy of immunity conferred by either previous infection or vaccination.

In the absence of the development and distribution of new vaccines, this would cause the number of COVID cases to rise once again (in the absence of renewed masking, social distancing, fast testing and contact tracing, lockdowns, and other virus suppression interventions).

The good news is that reduction in the number of COVID cases due to vaccination and previous infection could slow the mutation process, which occurs in infected individuals.

However, this will not be the case until a substantial percentage of the world’s population is vaccinated (with the exception of places like Taiwan, New Zealand and Australia, which can more easily close themselves off to international travel).

Time to herd immunity will also be further slowed by people refusing to take the vaccines, as well as vaccines’ less than 100% efficacy at preventing infection.

In light of these various pieces of new evidence, it seems likely (60% probability, +/- 10%) that we will continue to see the emergence of new “COVID waves” over the next 12 months.

“Super-Spreaders Out, Super-Spreading In: The Effects of Infectiousness Heterogeneity and Lockdowns on Herd Immunity”, by Tavori and Levy

SURPRISE

The authors note that most epidemiological models do not include differential infection via “superspreader” events. They argue that because of this, the actual threshold for effective herd immunity is much lower than the level estimated using traditional methods (often cited as 67% of the population previously infected or vaccinated).

On the other hand, the reduction in the number of potential superspreader events may be offset by the arrival of new SARS-CoV-2 variants that are much more transmissible.

While still uncertain, new research findings indicate that the B.1.1.7 variant of SARS-CoV-2 increase not only the transmissibility of the virus, but also the fatality rate for those infected.

SURPRISE

The following is from the 21Jan21) UK government brief (“NERVTAG Presented to SAGE” by Horby et al):

“1. The variant of concern (VOC) B.1.1.7 appears to have substantially increased transmissibility compared to other variants and has grown quickly to become the dominant variant in much of the UK.

2. Initial assessment by PHE of disease severity through a matched case-control study reported no significant difference in the risk of hospitalisation or death in people infected with confirmed B.1.1.7 infection versus infection with other variants.

3. Several new analyses are however consistent in reporting increased disease severity in people infected with VOC B.1.1.7 compared to people infected with non-VOC virus variants.

4. There have been several independent analyses of SGTF and non-SGTF cases identified through Pillar 2 testing linked to the PHE COVID-19 deaths line list:

a. LSHTM: reported that the relative hazard of death within 28 days of test for VOC-infected individuals compared to non-VOC was 1.35 (95%CI 1.08-1.68).

b. Imperial College London: mean ratio of CFR for VOC-infected individuals compared to non-VOC was 1.36 (95%CI 1.18-1.56) by a case-control weighting method, 1.29 (95%CI 1.07-1.54) by a standardised CFR method.

c. University of Exeter: mortality hazard ratio for VOC-infected individuals compared to non-VOC was 1.91 (1.35 - 2.71).

d. These analyses were all adjusted in various ways for age, location, time and other variables.

5. An updated PHE matched cohort analysis has reported a death risk ratio for VOC- infected individuals compared to non-VOC of 1.65 (95%CI 1.21-2.25).

6. There are several limitations to these datasets including representativeness of death data (<10% of all deaths are included in some datasets), power, potential biases in case ascertainment and transmission setting.

7. Based on these analyses, there is a realistic possibility that infection with VOC B.1.1.7 is associated with an increased risk of death compared to infection with non-VOC viruses.

8. It should be noted that the absolute risk of death per infection remains low.”

“SARS-Cov-2 RBD In Vitro Evolution Follows Contagious Mutation Spread, Yet Generates An Able Infection Inhibitor”, by Zahradnik et al from the Weizmann Institute of Science

SURPRISE

This very important research paper reports the results of experiments that attempt to predict the future emergence of even more infectious variants of SARS-CoV-2.

The authors first show how their approach predicts the emergence of two amino acid mutations on the virus’s protein spike that increase its ability to bond to human tissue (which increases transmissibility).

These are known as N501Y and E484K, which are present in the new UK, South African, and Brazilian variants.

Their key conclusion is that the emergence of another amino acid mutation, Q498R, on the spike protein could potentially increase transmissibility by a factor of 50x.

The good news is that this research also gives vaccine developers a jump on developing new formulations that will be effective against this mutation in the SARS-CoV-2 virus.

“COVID-19 Rarely Spreads Through Surfaces. So Why Are We Still Deep Cleaning?” by Dyani Lewis in Nature

“As evidence has accumulated over the course of the pandemic, scientific understanding about the virus has changed. Studies and investigations of outbreaks all point to the majority of transmissions occurring as a result of infected people spewing out large droplets and small particles called aerosols when they cough, talk or breathe. These can be directly inhaled by people close by.

“Surface transmission, although possible, is not thought to be a significant risk…

In fact, the US Centers for Disease Control and Prevention (CDC) clarified its guidance about surface transmission in May, stating that this route is “not thought to be the main way the virus spreads”. It now states that transmission through surfaces is “not thought to be a common way that COVID-19 spreads”…

“But it’s easier to clean surfaces than improve ventilation — especially in the winter — and consumers have come to expect disinfection protocols. That means that governments, companies and individuals continue to invest vast amounts of time and money in deep-cleaning efforts. By the end of 2020, global sales of surface disinfectant totaled US$4.5 billion, a jump of more than 30% over the previous year.”

After nearly a year’s delay, China finally let a WHO team into the country to investigate the origins of SARS-CoV-2. The results were controversial.

On 9 Feb, the WHO said the virus lab leak theory was “extremely unlikely”, claiming the most plausible explanation was that the virus jumped from bats to an “as yet unknown” intermediate host before infecting humans.

However, the very next day evidence emerged that Peter Daszak, one of the WHO researchers had worked with the Wuhan lab for 18 years, and had received grant funding from Chinese organizations.

Two days later, the Financial Times reported that the “US Raised ‘Deep Concerns’ Over WHO Report On Covid’s Wuhan Origins… ‘We have deep concerns about the way in which the early findings of the Covid-19 investigation were communicated and questions about the process,’ said Jake Sullivan, national security adviser… ‘It is imperative that this report be independent, with expert findings free from intervention or alteration by the Chinese government,’ Sullivan said.”

“The Lab-Leak Hypothesis”, by Nichoslson Baker in New York Magazine

SURPRISE

In this exhaustive analysis (which builds on reports in our previous Evidence Files), Baker concludes that, “What happened was fairly simple, I’ve come to believe. It was an accident. A virus spent some time in a laboratory, and eventually it got out. SARS-CoV-2, the virus that causes COVID-19, began its existence inside a bat, then it learned how to infect people in a claustrophobic mine shaft, and then it was made more infectious in one or more laboratories, perhaps as part of a scientist’s well-intentioned but risky effort to create a broad-spectrum vaccine. SARS-2 was not designed as a biological weapon. But it was, I think, designed.”

Note also that the Chinese government has denied the WHO team investigating the origins of SARS-CoV-2 access to the suspect Wuhan virology lab and its staff.

“Assessment Of The Risks Of Viral Transmission In Non-Confined Crowds”, by Garcia et al

“This work aims to assess the risks of Covid-19 disease spread in diverse daily-life situations (referred to as scenarios) involving crowds of unmasked pedestrians, mostly outdoors…

“Street cafés present the largest average rate of new infections caused by an attendant, followed by busy outdoor markets, and then metro and train stations, whereas the risks incurred while walking on fairly busy streets are comparatively quite low.

“Street cafés present the largest average rate of new infections caused by an attendant, followed by busy outdoor markets, and then metro and train stations, whereas the risks incurred while walking on fairly busy streets are comparatively quite low.”

“Epidemiology Of Post-COVID Syndrome Following Hospitalisation With Coronavirus: A Retrospective Cohort Study”, by Ayoubkhani et al from the UK Office of National Statistics

SURPRISE

There have been plenty of anecdotal reports about the long term mental and physical health effects of COVID, and the future additional costs they will impose on a healthcare system already facing a substantial increase in the number of elderly patients due to population aging.

The authors note that, “the epidemiology of post-COVID syndrome (PCS) is currently undefined.” Based on a study of 47,780 COVID patients, they “quantified rates of organ-specific impairment following recovery from COVID-19 hospitalisation compared with those in a matched control group”…

“Mean follow-up time was 140 days for COVID-19 cases and 153 days for controls. 766 (95% confidence interval: 753 to 779) readmissions and 320 (312 to 328) deaths per 1,000 person-years were observed in COVID-19 cases, 3.5 (3.4 to 3.6) and 7.7 (7.2 to 8.3) times greater, respectively, than in controls. Rates of respiratory, diabetes and cardiovascular events were also significantly elevated in COVID-19 cases, at 770 (758 to 783), 127 (122 to 132) and 126 (121 to 131) events per 1,000 person-years, respectively” …

The authors’ conclusion suggests that long-term costs to the healthcare system will be high, although more research is still needed.

“Conclusions: Individuals discharged from hospital following COVID-19 face elevated rates of multi-organ dysfunction compared with background levels, and the increase in risk is neither confined to the elderly nor uniform across ethnicities. The diagnosis, treatment and prevention of PCS require integrated rather than organ- or disease-specific approaches. Urgent research is required to establish risk factors for PCS.”

With new highly transmissible SARS-CoV-2 variants now appearing in the US (including those first identified in the UK, South Africa, Brazil, and now one in Ohio) we are in a deadly race.

If we can exponentially increase the number of people vaccinated, we may be able to limit the exponential increase in the number of people who will otherwise suffer COVID inflection, and eventually overwhelm hospital capacity without severe lockdowns, as we now see in Europe.

Unfortunately, the evidence to date has shown that US vaccinations have been increasing at a slow rate. For example, between 20Dec and 15Jan, the percent of the US population that had been vaccinated increased from 0.17% to 3.71%. In Israel, it went from 0.07% to 25.34%.

While the Biden administration promises to speed up vaccinations in the US, based on the rates at which infections by the new variants have grown in the UK, EU, South Africa, and Brazil, it seems very likely (80% probability) that more severe lockdowns and economic losses lie ahead.

If this forecast turns out to be wrong, it will be because of a dramatic improvement in the US vaccination rate over the next month.

SURPRISE

Adam Kurcarski, a London-based epidemiologist, posted this twitter thread explaining (mathematically) the risk posed by the more transmissible (i.e., infectious) new variants:

“Why a SARS-CoV-2 variant that's 50% more transmissible would in general be a much bigger problem than a variant that's 50% more deadly.

“As an example, suppose current R=1.1, infection fatality risk is 0.8%, generation time is 6 days, and 10k people infected (plausible for many European cities recently). So we'd expect 10000 x 1.1^5 x 0.8% = 129 eventual new fatalities after a month of spread.

“What happens if fatality risk increases by 50%? By above, we'd expect 10000 x 1.1^5 x (0.8% x 1.5) = 193 new fatalities.

“Now suppose transmissibility increases by 50%. By above, we'd expect 10000 x (1.1 x 1.5)^5 x 0.8% = 978 eventual new fatalities after a month of spread.

“The above is just an illustrative example, but the key message: an increase in something that grows exponentially (i.e. transmission) can have far more effect than the same proportional increase in something that just [linearly] scales an outcome.”

“Estimated Transmissibility And Severity Of Novel SARS-Cov-2 Variant Of Concern 202012/01 In England”, by Davies et al

SURPRISE

Further evidence about the increased transmissibility of the new SARS-CoV-2 strain in the UK.

“We estimate that [new variant of concern] VOC 202012/01 is 56% more transmissible (95% credible interval across three regions 50% -74%) than preexisting variants of SARS-CoV-2. We were unable to find clear evidence that VOC 202012/01 results in greater or lesser severity of disease than preexisting variants.

“Nevertheless, the increase in transmissibility is likely to lead to a large increase in incidence, with COVID-19 hospitalisations and deaths projected to reach higher levels in 2021 than were observed in 2020, even if regional tiered restrictions implemented before 19 December are maintained.

“Our estimates suggest that control measures of a similar stringency to the national lockdown implemented in England in November 2020 are unlikely to reduce the effective reproduction number R to less than 1, unless primary schools, secondary schools, and universities are also closed.

“We project that large resurgences of the virus are likely to occur following easing of control measures. It may be necessary to greatly accelerate vaccine roll-out to have an appreciable impact in suppressing the resulting disease burden.”

“Emergence and Rapid Spread Of A New Severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-Cov-2) Lineage With Multiple Spike Mutations In South Africa”, by Tegally et al

SURPRISE

Evidence about the new South African SARS-CoV-2 strain.

“Continued uncontrolled transmission of the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) in many parts of the world is creating the conditions for significant virus evolution. Here, we describe a new SARS-CoV-2 lineage (501Y.V2) characterised by eight lineage-defining mutations in the spike protein, including three at important residues in the receptor-binding domain (K417N, E484K and N501Y) that may have functional significance.

“This lineage emerged in South Africa after the first epidemic wave…[and] spread rapidly, becoming within weeks the dominant lineage in the Eastern Cape and Western Cape Provinces.

“Whilst the full significance of the mutations is yet to be determined, the genomic data, showing the rapid displacement of other lineages, suggest that this lineage may be associated with increased transmissibility.”

“Comprehensive Mapping Of Mutations To The SARS-Cov-2 Receptor-Binding Domain That Affect Recognition By Polyclonal Human Serum Antibodies”, by Greaney et al

SURPRISE

This paper finds that infection with previous strains of COVID is likely to provide less antibody-based immunity against the new South African and Brazilian variants of SARS-CoV-2. However, two caveats are in order.

First, it says nothing about immunity provided by T and B cells. Second, it says nothing about reduced severity of disease after reinfection. And third, it is possible to modify vaccines so that they are more effective against new variants of SARS-CoV-2, as we routinely do with seasonal influenza vaccines.

The authors note that, “the evolution of SARS-CoV-2 could impair recognition of the virus by human antibody-mediated immunity. To facilitate prospective surveillance for such evolution, we map how convalescent serum antibodies are impacted by all mutations to the spike’s receptor-binding domain (RBD), the main target of serum neutralizing activity. Binding by polyclonal serum antibodies is affected by mutations in three main epitopes in the RBD, but there is substantial variation in the impact of mutations both among individuals and within the same individual over time.

“Despite this inter- and intra-person heterogeneity, the mutations that most reduce antibody binding usually occur at just a few sites in the RBD’s receptor binding motif. The most important site is E484, where neutralization by some sera is reduced >10-fold by several mutations, including one in emerging viral lineages in South Africa and Brazil.”

“Vaccine Skepticism Among Medics Sparks Alarm In Europe And US”, in the Financial Times

SUPRPRISE

Given the expected increase in the prevalence of more transmissible variants of SARS-CoV-2, refusal of people to be vaccinated raises the probability of the health care system being overwhelmed in the absent of another strict lockdown, with its attendant negative impact on the economy.

“Signs that a relatively high number of healthcare workers are unwilling to receive the coronavirus vaccine in some parts of Europe and the US have alarmed politicians and health experts, as countries struggle to contain a surge in infections and carry out mass vaccination.”

“Incidence and Secondary Transmission of SARS-CoV-2 Infections in Schools”, by Zimmerman et al in the Journal of the American Academy of Pediatrics

SURPRISE

Learning losses caused by the closure of schools and shift to less effective remote learning will very likely have a negative long-term impact on productivity growth unless such losses are avoided or recovered. To enable schools to reopen and/or stay open, it is therefore critical to better understand how to measure, mitigate, and manage the risk of COVID infection in schools.

This study provides critical new evidence about this issue.

“Despite widely varying indoor air quality parameters, this large study found no child to adult transmission of the SARS-CoV-2 virus in schools. The risk of inflection could almost certainly be further reduced by improving indoor air quality in some schools.

“In an effort to mitigate the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), North Carolina (NC) closed its K–12 public schools to in-person instruction on 03/14/2020.

“On 07/15/2020, NC’s governor announced schools could open via remote learning or a “hybrid” model that combined in-person and remote instruction. In August 2020, 56 of 115 NC school districts joined the ABC Science Collaborative to implement public health measures to prevent SARS-CoV-2 transmission and share lessons learned.

“Over 9 weeks, 11 participating school districts had more than 90,000 students and staff attend school in-person; of these, there were 773 community-acquired SARS-CoV-2 infections documented by molecular testing.

“Through contact tracing, NC health department staff determined an additional 32 infections were acquired within schools. No instances of child-to-adult transmission of SARS-CoV-2 were reported within schools.”

Note that the data used in this study was collected before the emergence of more transmissible variants of SARS-CoV-2.

Note also that this study did not control for indoor air quality and HVAC conditions in school classrooms.

The extent to which masking, distancing, and high quality school HVAC systems can control infections caused by the new variants remains uncertain.

“Immunological Characteristics Govern the Transition Of COVID-19 To Endemicity”, by Lavine et a

SURPRISE

“We are currently faced with the question of how the SARS-CoV-2 severity may change in the years ahead.

“CoV-2 is an emerging virus that causes COVID. The virus has a high basic reproductive number (R0) and which is transmissible during the asymptomatic phase of infection, both of which make it hard to control.

“However, there are four human coronaviruses (HCoVs) that circulate endemically around the globe; they cause only mild symptoms and are not a significant public health burden…

“Our analysis of immunological and epidemiological data on endemic human coronaviruses (HCoVs) shows that infection-blocking immunity wanes rapidly, but disease-reducing immunity is long-lived [i.e., if you are infected, your sickness will be less severe].

“Our model, incorporating these components of immunity, recapitulates both the current severity of CoV-2 and the benign nature of (HCoVs), suggesting that once the endemic phase is reached and primary exposure is in childhood, CoV-2 may be no more virulent than the common cold.”

“UK Warns Of Threat From New Covid-19 Variant”, Financial Times

SURPRISE

Blaming the sudden resurgence of COVID infections across Europe on nations “letting down their guard too soon” has always seemed just a bit too convenient. And now a new hypothesis has emerged.

“According to Emma Hodcroft, an expert on viral genetics at the University of Bern in Switzerland, the new strain appears to have three mutations in the spike protein that the coronavirus uses to enter human cells. Two genetic letters have been deleted and another has been changed.”

This is potentially a very serious development, as the mutation appears to be significant. It increases uncertainty about the efficacy of the new vaccines that have been announced, as well as the degree of immunity obtained via prior COVID infection.

It also increases uncertainty about the speed at which the SARS-CoV-2 virus evolves. Up to now, the consensus seems to have been that this happens at a slower rate than the influenza virus (for which vaccine development is ongoing, and shots must be given annually to protect against new strains).

In so far as this latest mutation (and the apparent increase in infections that it may have caused) is consistent with the general path of viral evolution, increased transmissibility is usually accompanied by a decrease in the severity of infections.

“Immunological Memory To SARS-Cov-2 Assessed For Greater Than Six Months After Infection”, by Dan et al

SURPRISE

A critical uncertainty about the impact of COVID is how long immunity to it will likely last, either after recovery from infection or receipt of a vaccine.

This new study of how different components of our immune system react to COVID finds that protection against SARS-CoV-2 is likely to last longer than previously thought, for six months and possibly much longer.

However, immunity will also be affected by the future evolution of the SARS-CoV-2 virus. For example, because of the speed at which the influenza virus evolves, we need to get a different vaccine formulation each year. Time will tell whether that will be the case with SARS-CoV-2.

“Almost One in Five Americans May Have Been Infected with COVID-19” in The Economist

SURPRISE

If this new analysis is true, we are closer to achieving herd immunity that previously thought, which means a vaccination program could reduce the rate of infection more quickly than expected.

The herd immunity threshold is the percent of the population that has acquired immunity – either through infection or vaccination – that reduces the infection rate (reproduction number “R”) to a very low level.

The simple formula for the threshold is 1-1/R. So for an R of 1.5 (i.e., each infected person infects 1.5 more people), the herd immunity threshold is 33% of the population; for R=2.0, it is 50%, and for R=2.5 it is 60%.

To be sure, this simple formula is actually more complicated in practice (see references below). But in combination with last month’s news about vaccine effectiveness, the findings from the Economists’ analysis point towards a positive surprise.

“COVID-19 Herd Immunity: Where Are We?” by Fontanet and Cauchemez, and “Difficult to Determine Herd Immunity Threshold for COVID-19”, by Rita Rubin.

“Mobility Network Models of COVID-19 Explain Inequities and Inform Reopening”, by Chang et al

“Evidence of Long-Distance Droplet Transmission of SARS-CoV-2 by Direct Air Flow in a Restaurant in Korea”, by Kwon et al

These two new studies provides more evidence of the importance of careful management of HVAC and other indoor air quality variables to limit the transmission of SARS-CoV-2 in enclosed spaces.

The first study combines mobile phone location data with actual infection data to better understand the spread of COVID-19 in ten large US cities.

The authors find that, “a small minority of ‘superspreader’ points of interest [like indoor restaurants and fitness centers] account for a large majority of the infections, and that restricting the maximum occupancy at each point of interest is more effective than uniformly reducing mobility”…

The model “also correctly predicts higher infection rates among disadvantaged racial and socioeconomic groups solely as the result of differences in mobility: we find that disadvantaged groups have not been able to reduce their mobility as sharply, and that the points of interest that they visit are more crowded and are therefore associated with higher infection risk.”

The second paper focuses in great detail on infections that occurred during a short period of time in a restaurant. The authors highlight the critical importance of managing HVAC system variables to limit indoor infection spread.

“Naturally Occurring Indels In Multiple Coronavirus Spikes”, by Garry and Gallaher

This is the latest piece of evidence in the debate about whether SARS-CoV-2 had a natural or man-made origin. The authors argue for the former. They “compile evidence that insertion/deletion (indel) events at the S1/S2 and S2’ protease cleavage sites of the spike precursors are commonly occurring natural features of coronavirus evolution…[and] identify heretofore undescribed similarities in the S1/S2 and S2’ cleavage sites of multiple diverse coronavirus spikes that provide further evidence against a laboratory origin of SARS-CoV-2.”

Considering the profoundly negative implications of man-made origin, this is good news.

A new COVID-19 vaccine was announced, with a claim that it is 95% efficient at protecting against infection, after two doses, three months apart. However, it must be kept at extremely low temperature from the time it is manufactured until the time shots are administered. A remaining and as yet unknown uncertainty is how long the protection against infection conferred by the vaccine will last.

SUPRRISE
As analyzed in a previous feature article, many challenges stand between this announcement and any return to “normal” social and economic conditions.

The announcement also poses a risk that has largely gone unreported.

Consider what happened in the case of the large Black Lives Matter demonstrations following the death of George Floyd in Minneapolis on May 25, 2020.

Up to that point, controversy over wearing facemasks to prevent COVID inflection has mostly been confined to debate about its effectiveness. Resistance on ideological/political grounds existed, but was still confined to the fringe.

The appearance of large demonstrations of people not wearing masks, and, much worse, the refusal of many epidemiologists and others to condemn this behavior (because the cause was just) rather quickly led to the mass politicization of mask wearing, and buried stories about its effectiveness in preventing infection.

History will tell the impact this had on the intensity of subsequent waves of infections. In most complex adaptive systems, the effects of a perturbation are often both delayed and non-linear. The interaction of the BLM demonstrations, mask wearing, and infection rates are likely to be similar.

Which brings us to the new vaccine. A key risk is that it will provide people with a false sense of security, and in so doing cause many to relax effective measures like mask wearing and social distancing, which in turn will increase infections and the scale of the challenge vaccination must meet.

“Projected COVID-19 Epidemic In The United States In The Context Of The Effectiveness Of A Potential Vaccine And Implications For Social Distancing And Face Mask Use”, by Mingwang Shen et al

“The degree to which the US population can relax social distancing restrictions and face mask use will depend greatly on the effectiveness and coverage of a potential COVID-19 vaccine if future epidemics are to be prevented” …

“Without a vaccine, the spread of COVID-19 could be suppressed in these states by maintaining strict social distancing measures and face mask use levels. But relaxing social distancing restrictions to the pre-pandemic level without changing the current face mask use would lead to a new COVID-19 outbreak, resulting in 0.8-4 million infections and 15,000- 240,000 deaths across New York, Texas, Florida, and California states over the next 12 months.

“In this scenario, introducing a vaccine would partially offset this negative impact even if the vaccine effectiveness and coverage are relatively low.”

However, there is likely to be a dynamic relationship between vaccine strength and face mask use that will have a significant impact on pandemic control.

“If face mask use is reduced by 50%, a vaccine that is only 50% effective (weak vaccine) would require vaccination of 55-94% of the population to suppress the epidemic in these states.
“A vaccine that is 80% effective (moderate vaccine) would only require 32-57% coverage to suppress the epidemic.

“In contrast, if face mask usage stops completely, a weak vaccine would not suppress the epidemic, and further major outbreaks would occur. A moderate vaccine with coverage of 48-78% or a strong vaccine (100% effective) with coverage of 33-58% would be required to suppress the epidemic.”

SURPRISE
Based on this analysis, and given the reported strength (95% effective) of the new vaccine, if its introduction leads to a 50% drop in face mask use, somewhere between 33% and 60% of the population would have to be vaccinated to bring the pandemic under control.

“Covid-19 Herd Immunity Theory Dealt Blow By UK Research”, Financial Times

“The proportion of people in Britain with antibodies that protect against Covid-19 declined over the summer, according to research that adds to evidence that natural immunity can wane in a matter of months.

“The number of people with antibodies fell by a quarter, from 6 per cent of the population in June to 4.4 per cent in September, according to a study of hundreds of thousands of people, one of the largest of its kind to date.”

SURPRISE
This is an important finding that partially reduces a critical uncertainty: How long does naturally acquired immunity to COVID last?

It is only partial because it does not address the length of time that immunity based on T-Cells lasts. It also does not address how long immunity acquired through vaccination will last.

However, it does raise the likelihood that annual vaccinations against the SARS-CoV-2 virus may be required, as they are for influenza.

“Robust SARS-Cov-2-Specific T-Cell Immunity Is Maintained At 6 Months Following Primary Infection”, by Zuo et al

“The immune response to SARS-CoV-2 is critical in both controlling primary infection and preventing re-infection. However, there is concern that immune responses following natural infection may not be sustained and that this may predispose to recurrent infection.

“We analysed the magnitude and phenotype of the SARS-CoV-2 cellular immune response in 100 donors at six months following primary infection and related this to the profile of antibody level against spike, nucleoprotein and RBD over the previous six months…

“Median T-cell responses were 50% higher in donors who had experienced an initial symptomatic infection indicating that the severity of primary infection establishes a ‘setpoint’ for cellular immunity that lasts for at least 6 months.

“The T-cell responses to both spike and nucleoprotein / membrane proteins were strongly correlated with the peak antibody level against each protein…

“In conclusion, our data are reassuring that functional SARS-CoV-2-specific T-cell responses are retained at six months following infection although the magnitude of this response is related to the clinical features of primary infection.”

SURPRISE
Based on the responses of patients who have recovered from a COVID infection, this analysis finds that the T-Cell response is correlated with the antibody response and proportional to the severity of the initial infection.

The study also found that immunity lasts at least six months.
It is not yet clear if these findings will also apply to people who acquire immunity via vaccination rather than infection.

“Selective And Cross-Reactive SARS-Cov-2 T Cell Epitopes In Unexposed Humans”, by Jose Mateus et al

“Many unknowns exist about human immune responses to the SARS-CoV-2 virus. SARS-CoV-2–reactive CD4+ T cells have been reported in unexposed individuals, suggesting preexisting cross-reactive T cell memory in 20 to 50% of people.

“However, the source of those T cells has been speculative. Using human blood samples derived before the SARS-CoV-2 virus was discovered in 2019, we mapped 142 T cell epitopes across the SARS-CoV-2 genome to facilitate precise interrogation of the SARS-CoV-2–specific CD4+ T cell repertoire.

“We demonstrate a range of preexisting memory CD4+ T cells that are cross-reactive with comparable affinity to SARS-CoV-2 and the common cold coronaviruses…

“We find that variegated T cell memory to coronaviruses that cause the common cold may underlie at least some of the observed reactivity to SARS-CoV-2.”

SURPRISE
Exposure to the coronaviruses that cause common colds may be responsible for the T-Cell reactivity to the SARS-CoV-2 virus that has been observed in people who have not had COVID-19.

This raises intriguing questions about whether this T-Cell mediated resistance is higher in people who get more common colds, like students and teachers.

See also, “Preexisting and De Novo Humoral Immunity to SARS-CoV-2 in Humans”, by Ng et al

“Emergence And Spread Of A SARS-Cov-2 Variant Through Europe In The Summer Of 2020”, by Emma Hodcroft et al

“A variant of SARS-CoV-2 emerged in early summer 2020, presumably in Spain, and has since spread to multiple European countries. The variant was first observed in Spain in June and has been at frequencies above 40% since July. Outside of Spain, the frequency of this variant has increased from very low values prior to 15th July to 40-70% in Switzerland, Ireland, and the United Kingdom in September…

“Sequences in this cluster (20A.EU1) differ from ancestral sequences at 6 or more positions, including the mutation A222V in the spike protein and A220V in the nucleoprotein…

It is currently unclear whether this variant is spreading because of a transmission advantage of the virus or whether high incidence in Spain followed by dissemination through tourists is sufficient to explain the rapid rise in multiple countries.”

SURPRISE
A key uncertainty regarding SARS-CoV-2 is the rate at which it changes, via mutation and recombination. A related uncertainty is whether these changes will follow a common path for other viruses, increasing their transmissibility while reducing the severity of the illness they cause.

In so far as this is the case, then it increases the probability that control of SARS-CoV-2 will require ongoing vaccine research and development as well as annual vaccination, as is the case with influenza.

See also, “Spike mutation D614G alters SARS-CoV-2 Fitness”, by Jessica Plante

“Improving Survival of Critical Care Patients With Coronavirus Disease 2019 in England: A National Cohort Study, March to June 2020”, by Dennis et al

“There has been a substantial improvement in survival amongst people admitted to critical care with coronavirus disease 2019 in England, with markedly higher survival rates in people admitted in May and June compared with those admitted in March and April.”

“SARS-Cov-2 Seroprevalence And Transmission Risk Factors Among High-Risk Close Contacts: A Retrospective Cohort Study”, by Ng et al

“Between Jan 23 and April 3, 2020, 7770 close contacts (1863 household contacts, 2319 work contacts, and 3588 social contacts) linked to 1114 PCR-confirmed index cases were identified”...

“Among 7518 (96·8%) of the 7770 close contacts with complete data, the secondary clinical attack rate was 5·9% (95% CI 4·9–7·1) for 1779 household contacts, 1·3% (0·9–1·9) for 2231 work contacts, and 1·3% (1·0–1·7) for 3508 social contacts”…

“Sharing a bedroom and being spoken to by an index case for 30 min or longer were associated with SARS-CoV-2 transmission among household contacts.

“Among non-household contacts, exposure to more than one case, being spoken to by an index case for 30 minutes or longer, or sharing a vehicle with an index case were associated with SARS-CoV-2 transmission.

“Among both household and non-household contacts, indirect contact, meal sharing, and lavatory co-usage were not independently associated with SARS-CoV-2 transmission.”

SURPRISE
This study provides very useful data about the rates of COVID transmission among close contacts.
With the holiday season approaching, this study, along with new findings about the importance of indoor air quality, can be very helpful in reducing anxieties.

“Association Between Living With Children And Outcomes From COVID-19: An Opensafely Cohort Study Of 12 Million Adults In England”, by Harriet Forbes et al

“Among adults ≤65 years, living with children 0-11 years was not associated with increased risks of recorded SARS-CoV-2 infection, COVID-19 related hospital or ICU admission, but was associated with reduced risk of COVID-19 death (HR 0.75, 95%CI 0.62-0.92).

“Living with children aged 12-18 years was associated with a small increased risk of recorded SARS-CoV-2 infection (HR 1.08, 95%CI 1.03-1.13), but not associated with other COVID-19 outcomes…
“We observed no consistent changes in risk following school closure.”

SURPRISE
This very large study provides further support for keeping schools open to minimize students learning losses.

The percent of Americans who said they would definitely or probably get the COVID vaccine if it was available today dropped from 72% in May to 51% in September, according to Pew Research. The percent that said they would definitely not get the vaccine rose from 11% to 24% over the same period. Pew also found that, “Concern over side effects, uncertainty about effectiveness top reasons for those not planning to get a COVID-19 vaccine.”

SURPRISE
Gaining permanent control of the COVID pandemic is broadly a function of three variables: (1) the efficacy of a vaccine (including how it changes over time as the SARS-CoV-2 virus evolves; (2) the percentage of the population that is willing to take the vaccine; and (3) the natural development of herd immunity, as people become infected and survive.

This reduction in willingness to take the vaccine implies that the US will be struggling to gain control of the pandemic for longer than many people

“Covid-19: Do many people have pre-existing immunity? Population Immunity: Underestimated?” by Peter Doshi in the British Medical Journal 17Sep20

“Seroprevalence surveys measuring antibodies have been the preferred method for gauging the proportion of people in a given population who have been infected by SARS-CoV-2 (and have some degree of immunity to it), with estimates of herd immunity thresholds providing a sense of where we are in this pandemic.

“Whether we overcome it through naturally derived immunity or vaccination, the sense is that it won’t be over until we reach a level of herd immunity.
“The fact that only a minority of people, even in the hardest hit areas, display antibodies against SARS-CoV-2 has led most planners to assume the pandemic is far from over…

“But memory T cells are known for their ability to affect the clinical severity and susceptibility to future infection and the T cell studies documenting pre-existing reactivity to SARS-CoV-2 in 20-50% of people suggest that antibodies are not the full story…

“The research offers a powerful reminder that very little in immunology is cut and dried. Physiological responses may have fewer sharp distinctions than in the popular imagination: exposure does not necessarily lead to infection, infection does not necessarily lead to disease, and disease does not necessarily produce detectable antibodies.

“And within the body, the roles of various immune system components are complex and interconnected. B cells produce antibodies, but B cells are regulated by T cells, and while T cells and antibodies both respond to viruses in the body, T cells do so on infected cells, whereas antibodies help prevent cells from being infected.”

The rate at which herd immunity is naturally developing is another critical uncertainty.

Seroprevalence studies, which only measure the presence of antibodies, have almost certainly underestimated the percentage of the population that has already developed some degree of immunity.

The US Centers for Disease Control released updated estimates of the COVID-Infection Fatality Rate (IFR). This is the ration of COVID-19 related deaths to the estimated total number of people, both symptomatic and non-symptomatic, that have become infected (it is lower than the Case Fatality Rate, which uses only people who have tested positive for COVID-19 in the denominator).

The latest overall IFR estimate is 0.65% (65/100s of 1%).

In a separate analysis (“A Systematic Review And Meta-Analysis Of Published Research Data On COVID-19 Infection-Fatality Rates”), Myerowitz-Katz and Merone estimate an IFR of 0.68%, with a 95% confidence interval of 0.53% to 0.82%.

By comparison, estimated IFRs for seasonal influenza range from 0.10% to 0.18%. The estimated IFR from the 1957 H2N2 influenza pandemic is 0.67% and the 1918 pandemic greater that 2.5%. However, these estimates are noisy, because of considerably uncertainty about the percent of influenza infections that were non-symptomatic.

This is also a challenge for studies that estimate COVID’s IFR. Determining the number of people who have been infected is not easy, because not all who become infected develop antibodies that can be identified through serology testing. However, some infected people who don’t have antibodies develop a strong T-Cell immune response that requires a separate test to identify. Given the relatively limited scope of T-Cell testing thus far, we may still be overestimating COVID-19’s true IFR.

To a significant degree, the politicization of COVID-19 reflects an anxious public’s demand for reassurance when it comes to multiple uncertainties about the disease process itself, the percent of the population that has already been infected, the extent of immunity that confers (due to antibody and T-Cell responses), and, above all, SARS-CoV-2’s Infection Fatality Rate (IFR).

As more evidence has accumulated, estimates of COVID’s IFR have fallen. However thus far it is still above estimates of the IFRs for all but the 1918 influenza pandemic (after taking the likely percentage of non-symptomatic influenza cases into account).

So saying “COVID-19 is just like flu” is almost certainly incorrect. Yet that is a message that hasn’t been clearly communicated, which has allowed this issue to become highly polarized, and thus led to widely varying social responses (distancing, mask wearing, etc.) that are almost certainly prolonging the pandemic and worsening its economic consequences.

On 29 September, the Royal Society (the UK equivalent of the US National Academy of Sciences) released the most comprehensive analysis yet of indoor air quality issues related to the aerosol transmission of SARS-CoV-2, and, critically, how building HVAC systems can manage them (“The Ventilation Of Buildings And Other Mitigating Measures For COVID-19: A Focus On Winter 2020”).

SURPRISE
Aerosol transmission of SARS-CoV-2 and indoor air quality and HVAC issues have thus far in the COVID-19 crisis been relatively ignored. With the northern hemisphere heading into winter, these issues can no longer be ignored. This outstanding analysis shows how they can be managed (e.g., room CO2 monitors are good proxies for viral aerosol concentrations) – if building owners, school systems, and other parties take the issue seriously (and can afford the expense involved in upgrading HVAC systems and related management skills).

The flip side of this is that publication of this information also creates new causes for litigation if building owners fail to follow the Royal Society’s recommendations and someone falls ill. It is therefore almost certain that this will lead to further conflicts this winter between insurance carriers and building owners, which could slow the economic recovery from the COVID-19 shock.

Professor Limeng Yan of the University of Hong Kong published two papers setting out why she believes that SARS-CoV-2 was deliberately engineered by the Chinese government:

“Unusual Features of the SARS-CoV-2 Genome Suggesting Sophisticated Laboratory Modification Rather Than Natural Evolution and Delineation of Its Probable Synthetic Route” and “SARS-CoV-2 Is an Unrestricted Bioweapon: A Truth Revealed through Uncovering a Large-Scale, Organized Scientific Fraud.”

These reports attracted from support from apparently knowledgeable people, including Lawrence Sellin, PhD, a retired US Army Colonel who worked at the US Army Medical Research Institute for Infectious Diseases, and later in clinical research in the pharmaceutical industry. He notes that, “Since the beginning of the COVID-19 pandemic, the Chinese Communist Party supported by some Western scientists and a politically-motivated media have desperately tried to convince the world that the COVID-19 virus originated as a bat beta-coronavirus which underwent a natural mutation process and was then acquired by humans after exposure to infected animals.

"Undoubtedly, such subterfuge is meant to protect certain vested interests, including the potentially devastating political and economic consequences for China, global corporate and private investment in China and a negative effect on scientific collaboration and funding of major Western research laboratories…

“On February 3, 2020, ‘batwoman’ Dr. Zheng-Li Shi of the Wuhan Institute of Virology published an article suggesting that COVID-19 originated in bats and a bat coronavirus named RaTG13 was shown to be 96.2% identical to the COVID-19 virus, thus supporting the naturally-occurring theory.

“Since then, literally hundreds of scientific articles have used RaTG13 as a basis for investigating the natural origin of the COVID-19 pandemic, despite the fact that RaTG13 exists only on paper because no live virus or intact genome of RaTG13 have ever been isolated or recovered. Dr. Yan and her colleagues now make multiple arguments indicating that RaTG13 is a fabricated virus.”

Publication of the Yan reports also triggered critical responses. One of the most detailed (and condescending) is “In Response: Yan et Al Preprint Examinations of the Origin of SARS-CoV-2” by the Johns Hopkins University School of Public Health.

SURPRISE
Yan’s reports are not the first to claim that, either because of a lab accident that released a virus involved in “gain of function” studies, or because of the accidental release of a bioweapon under development, SARS-CoV-2 and the COVID-19 pandemic were not accidents of nature.

These claims have met with widespread resistance, by a range of authors who have studiously ignored asking why China continues to prevent international investigation of virology labs in Wuhan and the source of the virus.

Nor have they asked what is perhaps the most frightening question: If this virus was deliberately engineered (and either accidentally or deliberately released), “Cui Bono?”

Given the possible answers, and their potentially world changing implications, it is not hard to understand why so many choose to attack those who dare to challenge the conventional wisdom about the origins of the virus.

New research continues to give us a better understanding of COVID-19’s disease process and effects.

In “Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19)”, Puntmann et al found that 78% of the recovered COVID patients they tested had abnormal cardiovascular conditions compared to matched controls who had not been infected with COVID-19.

In “Cerebral Micro-Structural Changes in COVID-19 Patients”, Lu et al found “neurological symptoms were presented in 55% of COVID-19 patients.”

“A Mechanistic Model And Therapeutic Interventions For COVID-19 Involving A RAS-Mediated Bradykinin Storm” by Garvin et al summarizes the results of analysis undertaken using a supercomputer at the Oak Ridge National Laboratory. The authors conclude that a key part of COVID’s disease process is the increase it triggers in levels of the peptide bradykinin, which promotes inflammation and causes blood vessels to become leaky. In turn, this can account for the multiple cardiovascular, pulmonary, and neurological symptoms observed in COVID-19 patients. The good news is that the analysis also identified existing drugs that can be used to inhibit these “bradykinin storms.”

People who survive COVID-19 may end up with chronic long-term conditions that will limit their productivity and increase overall healthcare costs.
However, it appears that we may be closing in on better therapeutic approaches to limiting the development of these conditions in COVID-19 patients.

The broadest definition of the chance of death from a disease is the Infection Fatality Rate (IFR). While it is the one most people want to know, it is also the hardest to estimate. While the numerator (deaths) is known, the denominator (total people infected) is much more uncertain. The best way to estimate it is through seroprevalence studies, which test for the presence of disease antibodies in a statistically representative population sample.

However, other research has found that some people who tested positive for COVID failed to develop antibodies (though they did show a different response, based on their levels of so-called killer T-Cells). So in the case of COVID, IFRs based solely on seroprevalence (antibodies) are likely to be too high.

The largest COVID seroprevalence study conducted to date was recently published in the UK.

In “Antibody Prevalence For SARS-Cov-2 Following The Peak Of The Pandemic In England: REACT2 Study In 100,000 Adults”, Ward et al found that, “COVID prevalence of 6.0% (95% Confidence Interval: 5.8, 6.1). Highest prevalence was in London (13.0%), among people of Black or Asian (mainly South Asian) ethnicity (17.3%), and those aged 18-24 years (7.9%)… One third of antibody positive individuals reported no symptoms.”

The authors estimate that the overall IFR was 0.90%, with a 95% CI of (0.86, 0.94), with IFRs sharply increasing with patients’ age.

This contrasts with a previous estimated IFR (based on a meta-analysis of 36 smaller studies in different locations) of between 0% and 1.31%, with a median of 0.24% (“The Infection Fatality Rate Of COVID-19 Inferred From Seroprevalence Data”, by John Ioannidis).

Developing better estimates of the Infection Fatality Ratio for COVID is critical for making better risk management decisions (e.g., regarding the need for further quarantines).

While the new UK study is very important, the fact that some COVID patients fail to develop antibodies, while developing a strong killer T-Cell response, suggests that current IFR estimates are likely to be too high, but by still uncertain amount.

There were new warnings about what may happen when flu season arrives in the midst of our COVID pandemic.

See: “What Happens When COVID-19 Collides with Flu Season?” by Rita Rubin, and “COVID-19 and Flu, a Perfect Storm” by Belongia and Osterholm

In a worst case, hospitals could be overwhelmed, because the symptoms of the two diseases overlap.

However, thus far the southern hemisphere is having an extremely mild flu season, very likely because of the social distancing measures implemented to control the spread of COVID.

The most dangerous case is driven by the coinfection of people with both influenza and SARS-CoV-2 which could trigger recombinations in either or both viruses, and make them more transmissible and/or more deadly.

For example, SARS-CoV-2 is one of the largest and most complex of known RNA viruses. A recent paper described new research that found its RNA contains instructions for producing 23 new proteins in an infected cell whose function and effects in the disease process are still unknown (“The coding capacity of SARS-CoV-2”, by Finkel et al).

With students returning to schools and workers to offices, there is much more focus on COVID transmission via aerosols, and therefore on indoor air quality and the performance of HVAC systems.

For example, CDS and industry groups have recommended the use of MERV-13 filters and at least 6 air changes per hour (ACH), both of which significantly increase HVAC operating costs.

More sophisticated analyses are now appearing (like the ones below), whose estimation of inflection risk takes into account variables like the size of a room, the number of people in it, the length of time they are present, and the activities they are performing.
“Airborne Infection R-Numbers For Regularly Attended Spaces: COVID-19 A Case-Study”, by Burridge et al

“Estimation Of Airborne Viral Emission: Quanta Emission Rate Of SARS-Cov-2 For Infection Risk Assessment”, by Buonanno et al

“2019 Novel Coronavirus (COVID-19) Pandemic: Built Environment Considerations To Reduce Transmission”, by Dietz et al

“Can HVAC Systems Help Prevent Transmission of COVID-19?” by McKinsey & Company

SURPRISE
Before COVID arrived, there was significant evidence of the negative effects of poor indoor air quality in both office buildings and schools. See, for example:

“Associations of Cognitive Function Scores with Carbon Dioxide, Ventilation, and Volatile Organic Compound Exposures in Office Workers: A Controlled Exposure Study of Green and Conventional Office Environments”, by Allen et al

“Ventilation Rates In Recently Constructed U.S. School Classrooms”, by Batterman, et al

It is becoming clear that upgrading office and school HVAC systems to the new COVID infection prevention standards will very likely involve significant investment.

In the face of uncertain future demand for office space, some landlords may choose to forgo this investment, and hand their property over to lenders. This will increase the number of commercial loans in financial distress.

Shortcomings in school HVAC systems present even more problems. Because of the pressure to resume in-person schooling, school districts appear to be reluctant to fully disclose the current state of their HVAC systems. This will likely result in a growing amount of litigation, and either difficulties in renewing insurance coverage or increased payouts for districts that self-insure. In turn, this will make an already chaotic situation even worse, and further deepen students’ learning losses.

Two new papers illustrate the complex feedback loops that have arisen after the arrival of COVID, and how they have made controlling the pandemic even more difficult (in the absence of an effective vaccine).

In “An Epidemiological Model With Voluntary Quarantine Strategies Governed by Evolutionary Game Dynamics”, Amaral et al observe that, “During pandemic events, strategies such as quarantine and social distancing can be fundamental to curb viral spreading. Such actions can reduce the number of simultaneous infection cases and mitigate the disease spreading, which is relevant to the risk of a healthcare system collapse.

“Although these strategies can be suggested, or even imposed, their actual implementation may depend on the population perception of the risks associated with a potential infection. The current COVID-19 crisis is showing that some individuals are much more prone than others to remain isolated, avoiding unnecessary contacts, and respecting other restrictions.”

This leads to recurring waves of infections.

In “The Unintended Consequences Of Inconsistent Pandemic Control Policies”, Althouse et al show how inconsistent implementation of pandemic control measures produce results that are worse than no measures at all.

Evidence on the origin of the SARS-CoV-2 virus continues to accumulate and evolve.

The critical uncertainty is how the SARS-CoV-2 virus acquired a furin (an enzyme) cleavage on its spike protein of the virus, which facilitates its entry into human cells.

Previous research has found that the acquisition of the furin cleavage by H5 and H7 influenza viruses makes them much more infectious and deadly (e.g., “Cleavage Activation of the Influenza Virus Hemagglutinin and Its Role in Pathogenesis”, by Garten and Klenk). Recent research has found that this is also true for coronaviruses (see, “Furin Cleavage Site Is Key to SARS-CoV-2 Pathogenesis”, by Johnson et al.

However, no furin cleavage has been found to exist on the coronaviruses that are most genetically similar to SARS-CoV-2. So how did it get there?

At this point, there are at least three hypotheses. The first is that it occurred naturally, most likely via recombination with another circulating virus that coinfected the same animal or human organism (see, “A Palindromic RNA Sequence As A Common Breakpoint Contributor to Copy‑Choice Recombination In SARS‑COV‑2” by William Gallagher and “The Sarbecovirus Origin Of SARS-Cov-2’s Furin Cleavage Site”, by Spyros Lystras).

However, until this mysterious host is identified, a second hypothesis cannot be ruled out – that the virus originated in a laboratory (e.g., during a so-called “gain of function study” to assess how it could become more dangerous) and was released due to a lab accident (see, “Might SARS-CoV-2 Have Arisen via Serial Passage through an Animal Host or Cell Culture?”, by Sirotkin and Sirotkin). Gain of function studies are dangerous (see, “Why Do Exceptionally Dangerous Gain-of-Function Experiments in Influenza?”, by Mark Lipsitch), but the Wuhan Institute of Virology has in the past acknowledged performing them on bat coronaviruses.

There is also substantial evidence from around the world that lab accidents have occurred in the past (see, “Laboratory Escapes and ‘Self-fulfilling Prophecy’ Epidemics”, by Martin Furmanski). Moreover, China continues to resist international inspection and investigation of the Wuhan Institute of Virology.

However, the media has been notably reticent to investigate this hypothesis, more often than not dismissing the evidence supporting it as no more than a “conspiracy theory” (see, “Is Considering A Genetic Manipulation Origin For SARS-Cov-2 A Conspiracy Theory That Must Be Censored?”, by Rosanna Segreto).

However, evidence supporting this hypothesis has continued to accumulate. For excellent summaries, see “The Case Is Building That COVID-19 Had a Lab Origin” by Latham and Wilson.

This month, these authors published new evidence that (a) six miners in Mojiang, China (1,800 km from Wuhan) who became infected with a SARS like virus in 2012 (three of whom died) could have been the zoonotic host in which the furin cleavage was acquired via recombination; (b) the Wuhan Institute of Virology acquired samples of this virus; (c) it is possible that gain of functions were conducted on it; and (d) it is also possible that a sample from such a study escaped as the result of a lab accident (see, “A Proposed Origin for SARS-CoV-2 and the COVID-19 Pandemic”).

This (and perhaps other) evidence is apparently sufficiently compelling that the US National Institute of Health is now also pursuing this hypotheses more aggressively, “with specific attention to addressing…whether staff [at the Wuhan Virology Lab] had Sars-Cov-2 in their possession prior to December 2019” (see, “NIH Presses U.S. Nonprofit for Information on Wuhan Virology Lab”, Wall Street Journal, 19Aug20).

The third hypothesis is even scarier to contemplate, and has thus been almost completely dismissed by the media. That this virus was deliberately developed as a potential bioweapon by China, and intentionally released to disrupt the global economy, perhaps with the intention of lowering the risk to China of taking aggressive actions towards Hong Kong and Taiwan.

It is not hard to understand why few want to consider the implications of this hypothesis if it were ever proven to be true: Under US strategic doctrine, the deliberate use of SARS-CoV-2 would constitute an attack on the nation using a weapon of mass destruction (nuclear, chemical, and biological), which would invite retaliation using similar weapons.

Wuhan Institute of Virology in 2012, or subsequent gain of function studies; and (b) It was released via a laboratory accident, which Chinese authorities continue to cover up.
As the public becomes more aware of this body of evidence, conflict between China and many other nations will very likely substantially increase.

“The implications of silent transmission for the control of COVID-19 outbreaks”, by Moghadas et al

SURPRISE
The authors estimate that “the majority of incidences may be attributable to silent transmission from a combination of the presymptomatic stage and asymptomatic infections.”
“Consequently, even if all symptomatic cases are isolated, a vast outbreak may nonetheless unfold. We further quantified the effect of isolating silent infections in addition to symptomatic cases, finding that over one-third of silent infections must be isolated to suppress a future outbreak below 1% of the population.”

This implies that, in the absence of an effective and widely deployed coronavirus vaccine, in-home testing (or improved wearable sensor technology) that quickly identifies people infected with the virus will be critical to its long-term control.

So too is control of potential superspreading events, which raises the subjects of aerosol based transmission of SARS-CoV-2 and indoor air quality.

There has been increasing debate over whether and to what extent SARS-CoV-2 is being transmitted via aerosols

SURPRISE
In “Airborne Transmission of of SARS-CoV-2 Theoretical Considerations and Available Evidence”, Klompas et al note that, “The coronavirus disease 2019 (COVID-19) pandemic has reawakened the long-standing debate about the extent to which common respiratory viruses, including the severe acute respiratory syndrome coronavirus2 (SARSCoV-2), are transmitted via respiratory droplets vs aerosols. Droplets are classically described as larger entities (>5μm) that rapidly drop to the ground by force of gravity, typically within 3 to 6 feet of the source person.

“Aerosols are smaller particles (<5 μm) that rapidly evaporate in the air, leaving behind droplet nuclei that are small enough and light enough to remain suspended in the air for hours (analogous to pollen).

“Determining whether droplets or aerosols predominate in the transmission of SARS-CoV-2 has critical implications”…

“Investigators have demonstrated that speaking and coughing produce a mixture of both droplets and aerosols in a range of sizes, that these secretions can travel together for up to 27 feet, that it is feasible forSARS-CoV-2 to remain suspended in the air and viable for hours, that SARS-CoV-2 RNA can be recovered from air samples in hospitals, and that poor ventilation prolongs the amount of time that aerosols remain airborne.

“Many of these same characteristics have previously been demonstrated for influenza and other common respiratory viruses. These data provide a useful theoretical framework for possible aerosol-based transmission for SARS-CoV-2, but what is less clear is the extent to which these characteristics lead to infections.

“Demonstrating that speaking and coughing can generate aerosols or that it is possible to recover viral RNA from air does not prove aerosol-based transmission; infection depends as well on the route of exposure, the size of inoculum, the duration of exposure, and host defenses.

“Notwithstanding the experimental data suggesting the possibility of aerosol-based transmission, the data on infection rates and transmissions in populations during normal daily life are difficult to reconcile with long-range aerosol-based transmission.

“First, the reproduction number for COVID-19 before measures were taken to mitigate its spread was estimated to be about 2.5, meaning that each person withCOVID-19 infected an average of 2 to 3 other people. This reproduction number is similar to influenza and quite different from that of viruses that are well known to spread via aerosols such as measles, which has a reproduction number closer to 18.

“Considering that most people with COVID-19 are contagious for about 1week, a reproduction number of 2 to 3 is quite small given the large number of interactions, crowds, and personal contacts that most people have under normal circumstances within a 7-day period.

“Either the amount of SARSCoV-2 required to cause infection is much larger than measles or aerosols are not the dominant mode of transmission.

“Similarly, the secondary attack rate for SARS-CoV-2 is low. Case series that have evaluated close contacts of patients with confirmedCOVID-19 have reported that only about 5% of contacts become infected.

“However, even this low attack rate is not spread evenly among close contacts but varies depending on the duration and intensity of contact. The risk is highest among household members, in whom transmission rates range between 10% and 40%. Close but less sustained contact such as sharing a meal is associated with a secondary attack rate of about 7%, whereas passing interactions among people shopping is associated with a secondary attack rate of 0.6%...

“This pattern seems more consistent with secretions that fall rapidly to the ground within a narrow radius of the infected person rather than with virus-laden aerosols that remain suspended in the air at face level for hours where they can be inhaled by anyone in the vicinity.

“An exception may be prolonged exposure to an infected person in a poorly ventilated space that allows otherwise insignificant amounts of virus-laden aerosols to accumulate [as in the case of almost all documented superspreader events]…

“All told, current
understanding about SARS-CoV-2 transmission is still limited. There are no perfect experimental data proving or disproving droplet vs. aerosol-based transmission of SARSCoV- 2. The balance of evidence, however, seems inconsistent with aerosol-based transmission of SARS-CoV-2 particularly in well-ventilated spaces.”

The debate over aerosol transmission, and the reopening of the economy, has increased the focus on indoor air quality

In “How to Make Indoor Air Safer”, Kaleigh Rogers finds that, “When people are outside, aerosol transmission is less of a concern because in wide-open spaces, these particles are quickly dispersed and diluted, making it difficult for an infectious concentration to accumulate.”

Indoors, “you can achieve an air change by one of two ways…The first is “through the gross changeout of air, bringing in outside air and exhausting air from the room. Or you can achieve it by using high-efficiency filters that effectively remove virus-containing particles from the air”…

“Guidelines from the Centers for Disease Control and Prevention, which were published before the COVID-19 pandemic, outline exactly what standards buildings need to have to achieve “airborne infection isolation,” which means stopping the spread of aerosols smaller than 5 microns.

“At a minimum, buildings need to be reaching six air changes per hour, according to these CDC guidelines…The average commercial building now only performs one or two air changes per hour, and could squeeze in another with an air filtration system. The other four and a half or five air changes per hour, you’re really going to have to rely on in-room, stand-alone, HEPA filter air cleaners.”

However, in “Why Aren’t We Talking About Ventilation”, Zeynep Tufekci concludes that, “six months into a respiratory pandemic, we are still doing little to mitigate airborne transmission.”

See also, “Can HVAC systems help prevent transmission of COVID-19?” by McKinsey & Company

“US lab giant warns of new Covid-19 testing crunch in autumn”, by David Crow in the Financial Times

SURPRISE
“The largest laboratory company in the US has warned it will be impossible to increase coronavirus testing capacity to cope with demand during the autumn flu season, in a sign that crippling delays will continue to hamper the US response to the pandemic.”

James Davis, from Quest Diagnostics, is quoted as saying that, “it will be impossible to increase coronavirus testing capacity to cope with demand during the autumn flu season… but it’s not the labs that are the bottleneck. [It] is our ability to get physical machines and, more importantly, our ability to feed those machines with chemical reagents.”

A separate analysis by Reuters concluded that, “public health officials are not addressing this core supply-chain problem” (“The U.S. has more COVID-19 testing than most. So why is it falling so short?”).

Two new analyses find that the importance of population heterogeneity to COVID spread and the threshold required for herd immunity has been underestimated.

SURPRISE
This new research implies that we may be closer to a downward turn in the pandemic than previously believed.

In “Persistent Heterogeneity Not Short-Term Overdispersion Determines Herd Immunity To COVID-19”, Tkachenko et al observe that, “It has become increasingly clear that the COVID-19 epidemic is characterized by overdispersion whereby the majority of the transmission is driven by a minority of infected individuals.

“Such a strong departure from the homogeneity assumptions of traditional models is usually hypothesized to be the result of short-term super-spreader events, such as an individual’s extreme rate of virus shedding at the peak of infectivity while attending a large gathering without appropriate mitigation.

“However, heterogeneity can also arise through long-term, or persistent variations in individual susceptibility or infectivity.”

Most existing epidemiological models (e.g., Susceptible-Infected-Recovered) assume a homogenous population composed of identical individuals. When a model assumes a heterogenous population (e.g., in which individuals differ in terms of the strength of their immune system, their propensity to socialize, and the size of the contact networks with which they have regular interactions), the important new effects are observed.

“Persistent heterogeneity has three important consequences compared to the effects of overdispersion: (1) It results in a major modification of the early epidemic dynamics; (2) It significantly suppresses the herd immunity threshold; (3) It significantly reduces the final size of the epidemic.”

In “Power-Law Population Heterogeneity Governs Epidemic Waves”, Neipel et al examine German data and also “find that in strongly heterogeneous populations the epidemic reaches only a small fraction of the population. This implies that the herd immunity level can be much lower than in commonly used models with homogeneous populations.”

Recent studies have provided more information about the long term effects of a COVID-19 infection.

SURPRISE

In “The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings”, Paterson et al conclude that, “Preliminary clinical data indicate that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with neurological and neuropsychiatric illness.”

Other studies are finding that some patients are taking a very long time to recover from COVID-19, which has implications for longer term health care costs and employment effects (see, “Many Stay Sick After Recovering From Coronavirus” by Duhm and Hackenbroch in Der Spiegel.

A SARS-CoV-2 mutation (D614G) is believed to have increased the transmissibility of the virus.

See, “The D614G mutation in the SARS-CoV-2 spike protein reduces S1 shedding and increases infectivity”, by Zhang et al

It is not yet clear whether the mutation has affected the Infection and Case Fatality Rates. In the case of other viruses, these usually decline as transmissibility increase.

In addition to environmental factors (e.g., frequent use of public transportation), gender (men), age (elderly), and comorbidities (e.g., hypertension and obesity), new research has also pointed to genetic factors that likely affect the Infection Fatality Rates (and more narrowly defined Case Fatality Rates) for different groups.

SURPRSE

In “OpenSAFELY: factors associated with COVID-19 death in 17 million patients”, Williamson et al find that Black and South Asian people are at higher risk, even after adjusting for all other factors.

There were multiple new papers related to COVID-19 immunity issues

SURPRISE

Some highlighted the inaccuracy of seroprevalance tests for antibodies in people who have had COVID-19. Others noted wide variation in how many antibodies develop, and how long they last in patients’ blood. Still others highlighted the continued uncertainty about the extent of immunity antibodies provide.

The most encouraging news was the discovery of increases in so-called killer T-cells that also help fight infections, even in people who did not have antibodies but had been exposed to COVID-19.

It remains to be seen how much immunity they confer, and how long that will last (e.g., see, “Immunity to COVID-19 is probably higher than tests have shown”, by Katarina Sternudd of the Karolinska Institute).

“Analysis of hospital traffic and search engine data in Wuhan China indicates early disease activity in the Fall of 2019”, by Nsoesie et al

SURPRISE

“Early investigations into SARS-CoV-2 emergence and the resulting COVID-19 disease outbreak proposed the proximate cause was a zoonotic spillover event in late November or early December 2019 in Wuhan, China…

“However, recent evidence suggests that the virus may have already been circulating at the time of the outbreak. Here we use previously validated data streams - satellite imagery of hospital parking lots and Baidu search queries of disease related terms - to investigate this possibility. We observe an upward trend in hospital traffic and search volume beginning in late Summer and early Fall 2019. While queries of the respiratory symptom “cough” show seasonal fluctuations coinciding with yearly influenza seasons, “diarrhea” is a more COVID-19 specific symptom and only shows an association with the current epidemic.

“The increase of both signals precedes the documented start of the COVID-19 pandemic in December.”

“Bounding the Predictive Values of COVID-19 Antibody Tests” by Charles F. Manski

SURPRISE

“COVID-19 antibody tests have imperfect accuracy. There has been lack of clarity on the meaning of reported rates of false positives and false negatives. For risk assessment and clinical decision making, the rates of interest are the positive and negative predictive values of a test.

“Positive predictive value (PPV) is the chance that a person who tests positive has been infected. Negative predictive value (NPV) is the chance that someone who tests negative has not been infected. The medical literature regularly reports different statistics, sensitivity and specificity. Sensitivity is the chance that an infected person receives a positive test result. Specificity is the chance that a non-infected person receives a negative result.

Knowledge of sensitivity and specificity permits one to predict the test result given a person’s true infection status.
“These predictions are not directly relevant to risk assessment or clinical decisions, where one knows a test result and wants to predict whether a person has been infected.

“Given estimates of sensitivity and specificity, PPV and NPV can be derived if one knows the prevalence of the disease, the rate of illness in the population. PPV increases with prevalence, and NPV decreases… [However] there is still considerable uncertainty about the prevalence of COVID-19”…

“The FDA estimates of PPV-NPV assuming that the population infection rate is 0.05 [5% of the population]. However this estimate is not well grounded”…

Manski “addresses the problem of inference on the PPV and NPV of FDA approved COVID-19 antibody tests given estimates of their sensitivity and specificity and credible bounds on prevalence.”

Manski finds that the very wide bounds on various estimates of population prevalence (from 1.7% to 61.8%) have a substantial impact on PPV and NPV.

He concludes that, “COVID-19 antibody tests have imperfect accuracy…Persons receiving negative test results can be reasonably confident that they do not have antibodies to COVID-19. In contrast, the estimated bounds on PPV have widths ranging from about 40% to 70%, with even wider confidence intervals. The upper bounds are all near 100%.

“The problem for risk assessment is that the lower bounds are quite low in magnitude, being 60.4%, 28.9%, and 55.9%. The lower bounds of the confidence intervals are considerably lower still. Thus, persons receiving positive test results should not be confident that they have antibodies to COVID-19.”

“COVID-19: in the footsteps of Ernest Shackleton”, by Ing et al

SURPRISE

This paper shows why, in the absence of much wider testing, the presence of a high percentage of asymptomatic people infected with COVID-19 leads to a high current level of uncertainty about its population prevalence.

“We describe what we believe is the first instance of complete COVID-19 testing of all passengers and crew on an isolated cruise ship during the current COVID-19 pandemic. Of the 217 passengers and crew on board, 128 tested positive for COVID-19 (59%).

“Of the COVID-19-positive patients, 19% (24) were symptomatic; 6.2% (8) required medical evacuation; 3.1% (4) were intubated and ventilated; and the mortality was 0.8% (1).

“The majority of COVID-19-positive patients were asymptomatic (81%, 104 patients). We conclude that the prevalence of COVID-19 on affected cruise ships is likely to be significantly underestimated.”

“Estimating the overdispersion in COVID-19 transmission using outbreak sizes outside China”, by Endo et al

This paper finds that control of superspreading events – which has been the focus of Japan’s efforts to combat the virus -- is critical to reducing population transmission of COVID-19.

“Not all symptomatic cases of COVID-19 cause a secondary transmission, which was also estimated to be the case for past coronavirus outbreaks (SARS/MERS).

“Finding high individual-level variation (i.e. overdispersion) in the distribution of the number of secondary transmissions, which can lead to so-called superspreading events, is crucial information for epidemic control”…

It “suggests that most cases do not contribute to the expansion of the epidemic, which means that containment efforts that can prevent superspreading events have a disproportionate effect on the reduction of transmission.”

“Estimating Probabilities of Success of Vaccine and Other Anti-Infective Therapeutic Development Programs”, by Lo et al

SUPRRISE

This new paper provides valuable base rate data for use in forecasting the probability that an effective SARS-CoV2 vaccine will be developed.

“A key driver in biopharmaceutical investment decisions is the probability of success of a drug development program. We estimate the probabilities of success (PoSs) of clinical trials for vaccines and other anti-infective therapeutics using 43,414 unique triplets of clinical trial, drug, and disease between January 1, 2000, and January 7, 2020, yielding 2,544 vaccine programs and 6,829 nonvaccine programs targeting infectious diseases”…

“The overall estimated PoS for an industry-sponsored vaccine program is 39.6%, and 16.3% for an industry-sponsored anti- infective therapeutic” …

“Viruses involved in recent outbreaks—Middle East respiratory syndrome (MERS), severe acute respiratory syndrome (SARS), Ebola, and Zika—have had a combined total of only 45 nonvaccine development programs initiated over the past two decades, and no approved therapy to date.”

“Revealed: The Long Term Severe Effects of COVID-19 that Could Go On for Months”, by Georgina Hayes in The Telegraph

See also, “Grief, Lockdown, and Coronavirus: A Looming Mental Health Crisis” by Emma Jacobs in the Financial Times

SARS-CoV2 is a new coronavirus, and it is becoming clear that we still have much to learn about its long-term physical and psychological effects on people who have had COVID-19 and survived, and/or are grieving for people who have died from it.

Increasingly, we see reports like these in the Telegraph and FT, which describe a wide range of physical and mental health symptoms that are appearing months after coming down with COVID-19.

This represents a significant uncertainty in many areas, from healthcare costs to reopening and people’s ongoing employment prospects.

“A Deadly Mosquito-Borne Illness Is Brewing in the Northeast” by Oscar Schwartz

SURPRISE

Eastern equine encephalitis (EEE) virus is transmitted by mosquito bites and causes severe brain infection. The case fatality rate is around 40%.

While EEE cases are still rare, the 2019 outbreak of EEE in the Northeast United States was one of the most severe on record.

The author concludes that the number of people contracting EEE may increase in the future, as “today, the Northeast is among the fastest-warming regions in the United States, its milder winters and intense summers ever more conducive to abundant mosquito populations.”

“Viruses and volatility — how uncertainty impacts on our health”, by John Coates in the Financial Times

“Increased uncertainty (or volatility) leads to elevated levels of cortisol, the stress hormone. Prolonged uncertainty, as we’re experiencing with COVID19, can lead to a range of [physical and mental] health problems, as well as large decrease in risk appetite.”

Both the health problems and the decline in risk appetite will act as restraints on future labor productivity and economic growth. They will also almost certainly cause social and political effects. The most likely is greater demand for various dimensions of security.

“Estimating SARS-CoV-2 seroprevalence and epidemiological parameters with uncertainty from serological surveys”, by Larremore et al

“Serological testing is a critical component of the response to COVID-19 as well as to future epidemics. Assessment of population seropositivity, a measure of the prevalence of individuals who have been infected in the past and developed antibodies to the virus, can address gaps in knowledge of the cumulative disease incidence. This is particularly important given inadequate viral diagnostic testing and incomplete understanding of the rates of mild and asymptomatic infections. In this context, serological surveillance has the potential to provide information about the true number of infections, allowing for robust estimates of case and infection fatality rates and for the parameterization of epidemiological models to evaluate the possible impacts of specific interventions and thus guide public health decision-making…

“Three sources of uncertainty complicate efforts to learn population seroprevalence from subsampling.

“First, tests may have imperfect sensitivity and specificity; estimates for COVID-19 tests on the market as of April 2020 reported specificity between 95% and 100% and sensitivity between 62% and 97%.

“Second, the population sampled will likely not be a representative random sample, particularly in the first rounds of testing, when there is urgency to test using convenience samples and potentially limited serological testing capacity.

“Third, there is uncertainty inherent to any model-based forecast which uses the empirical estimation of seroprevalence, regardless of the quality of the test, in part because of the uncertain relationship between seropositivity and immunity.”

“What Antibody Studies Can Tell You – And What They Can’t”, by Caroline Chen, ProPublica

SURPRISE

“Herd immunity is when the vast majority of a given population have been infected. In such situations, the virus has a hard time infecting the remaining people, because there aren’t enough carriers to reach them.

“In order to achieve herd immunity, scientists say that a community would need to have at least 60% of its population infected. That’s the lowest estimate I’ve been told. Other scientists have told me 80% to 90%. The reason this percentage isn’t precisely known is because it depends on things like exactly how contagious the virus is and also whether people who have been infected are immune forever, or if they lose immunity after a while, which researchers also are furiously working to figure out.”

Note: The higher the Basic Reproductive Number (R0), the higher the proportion of the population that needs to be immune to stop its spread. This is known as the herd immunity threshold, and the formula for
finding it is actually pretty straightforward: 1 – 1/R0.

E.g., “Assessment of the SARS-CoV-2 basic reproduction number, R0, based on the early phase of COVID-19 outbreak in Italy”, by D’Arienzo and Conglio found a 95% Confidence Interval of 2.43 to 3.10.

In “High Contagiousness and Rapid Spread of Severe Acute Respiratory Syndrome Coronavirus 2” Sanche et al from Los Alamos National Laboratory found a 95% CI for R0 of 3.8 to 8.9, with a median of 5.7

So far, estimates of COVID19’s reproductive number vary widely (see: “Modeling the Heterogeneity of COVID19’s Reproductive Number, and Its Impact on Predictive Scenarios” by Donnat and Holmes from Stanford University).

The ProPublica article notes that no studies have reported levels of infection anywhere near high enough to confer herd immunity on a population.

Chen writes that, “the highest rate I’ve seen is in Chelsea, Massachusetts, the epicenter of the coronavirus outbreak in that state. Researchers at Massachusetts General Hospital tested 200 pedestrians and found about a third had antibodies…

“On April 23, NY Governor Andrew Cuomo announced preliminary data from the state’s serosurvey,
saying that 13.9% of state residents had tested positive for antibodies. In New York City, it was about 21%...

Chen concludes, “the other way to achieve herd immunity is via a vaccine, which is far safer and doesn’t involve millions of people getting sick. But developing vaccines is a slow process, so achieving herd immunity that way won’t happen any time soon.”

“Asymptomatic Transmission, the Achilles’ Heel of Current Strategies to Control Covid-19”, by Gandhi et al in the New England Journal of Medicine

“Traditional infection-control and public health strategies rely heavily on early detection of disease to contain spread. When Covid-19 burst onto the global scene, public health officials initially deployed interventions that were used to control severe acute respiratory syndrome (SARS) in 2003, including symptom-based case detection and subsequent testing to guide isolation and quarantine.

“This initial approach was justified by the many similarities between SARS-CoV-1 and SARSCoV-2, including high genetic relatedness, transmission primarily through respiratory droplets, and the frequency of lower respiratory symptoms (fever, cough, and shortness of breath) with both infections developing a median of 5 days after exposure.
“However, despite the deployment of similar control interventions, the trajectories of the two epidemics have veered in dramatically different directions.

“Within 8 months, SARS was controlled after SARS-CoV-1 had infected approximately 8100 persons in limited geographic areas.

“Within 5 months, SARS-CoV-2 has infected more than 2.6 million people and continues to spread rapidly around the world.

“What explains these differences in transmission and spread? A key factor in the transmissibility of Covid-19 is the high level of SARS-CoV-2 shedding in the upper respiratory tract, even among presymptomatic patients, which distinguishes it from SARS-CoV-1, where replication occurs mainly in the lower respiratory tract…

“Ultimately, the rapid spread of Covid-19 across the United States and the globe, the clear evidence of SARS-CoV-2 transmission from asymptomatic persons, and the eventual need to relax current social distancing practices argue for broadened SARS-CoV-2 testing to include asymptomatic persons in prioritized settings. These factors also support the case for the general public to use face masks when in crowded outdoor or indoor spaces.”

“A mysterious blood-clotting complication is killing coronavirus patients”, by Ariana Cha, Washington Post

SURPRISE

“Accumulating research findings suggest that COVID19 is more than a respiratory virus, and in fact attacks the body in other ways. In analyzing comorbidities that affect COVID19 mortality, recent data and analyses find that pre-existing cardiovascular conditions increase risk far more than asthma.”

“An analysis of SARS-CoV-2 viral load by patient age”, by Jones et al

This is an important indicator as many states and nations struggle with the decision of when and how to reopen schools.
“Data on viral load, as estimated by real-time RT-PCR threshold cycle values from 3,712 COVID-19 patients were analysed to examine the relationship between patient age and SARS-CoV-2 viral load.

“Analysis of variance of viral loads in patients of different age categories found no significant difference between any pair of age categories including children. In particular, these data indicate that viral loads in the very young do not differ significantly from those of adults. Based on these results, we have to caution against an unlimited re-opening of schools and kindergartens in the present situation. Children may be as infectious as adults.”

“SARS-CoV-2 through the postpandemic period”, by Kissler et al

SURPRISE

“It is urgent to understand the future of severe acute respiratory syndrome– coronavirus 2 (SARS-CoV-2) transmission. We used estimates of seasonality, immunity, and cross-immunity for betacoronaviruses OC43 and HKU1 from time series data from the USA to inform a model of SARS-CoV-2 transmission.

“We projected that recurrent wintertime outbreaks of SARSCoV- 2 will probably occur after the initial, most severe pandemic wave.

“Absent other interventions, a key metric for the success of social distancing is whether critical care capacities are exceeded. To avoid this, prolonged or intermittent social distancing may be necessary into 2022.”

“Coronavirus as a Strategic Challenge: Has Washington Missed the Problem” by Graham Allison

Allison challenges our thinking with a classic “Team B” analysis that is solidly grounded in the current evidence about COVID19 and its effects.

“Stepping back, while it may seem insensitive, to assess the magnitude of the threat to the nation that has so far led to choices that have pushed what had been a robust economy into what markets expect will be the deepest contraction since the Great Depression, it is nonetheless necessary to look at the big picture.

“In round numbers, BC [Before COVID19], according to actuarial tables, 3 million Americans were expected to die in 2020. If AC [After COVID19] that number grows by 100,000 to 3.1 million, how should we assess the significance of that?

“For each of these individuals and their families and friends, of course, each death is a great tragedy. As John Donne taught us, every man or woman’s death “diminishes me.”

“At the same time, for those who set life insurance rates, produce actuarial tables, and make judgments about hospital capacity, an additional 100,000 deaths would not require any change left of decimal place.

“Brute facts are hard to ignore. In the world BC, how many Americans were dying daily from other causes? Roughly, 8,000. That means that in the 50 days since the first death from Coronavirus in which it claimed an additional 32,000 lives in the U.S., 400,000 of our fellow citizens died from other causes. The coronavirus death toll is thus roughly 4 days of “normal” deaths BC.”

The COVID19 pandemic continues to spread around the world, with the worst casualties very likely yet to come when it hits emerging economies in full force. A critical issue is when developing nations will be able to sufficiently reduce its impact to allow their economies to begin a recovery process that will very likely be long and difficult. We see four possible scenarios of increasing length, whose realization depends on the resolution of a limited number of critical uncertainties.

(1) Development of a much more effective therapeutic intervention for patients with severe COVID symptoms. Shortest time to restart.

(2) Largescale deployment of serological tests that finds large number have had COVID19, and now have immunity that should last at least until estimated vaccine or improved therapeutic scale up.

(3) Seasonal drop in coronavirus transmission and COVID19 cases, and largescale deployment of active infection testing that allows effective contact tracing and isolation until vaccine &/or improved therapeutic scale up.

(4) No seasonal drop in transmission; slow deployment of serological and active case testing; slow development of improved therapeutic intervention and vaccine. Longest time to economic restart.

Uncertainty: Efficacy of therapeutic interventions

Early reports from China reported mortality rates for ICU admitted COVID19 patients above 80%. However, a recent study found that in Italy the rate was 26% (“Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy”, by Grasselli et al).

Another report found preliminary indications of the effectiveness of the antiviral drug remdesivir (Compassionate Use of Remdesivir for Patients with Severe Covid-19, by Grein et al in the New England Journal of Medicine).

So there is evidence that therapeutic interventions are improving. However, the efficacy of many therapeutic interventions (e.g., experimental antiviral drugs) has yet to be conclusively demonstrated. See, “A Look at the Treatments Currently Being Used against the Coronavirus”, Der Spiegel, 9Apr20

Uncertainties: Serological (antibody) testing deployment, to estimate the extent and strength of herd immunity already present in the population.

Serological tests are not yet available in large numbers, and have not been done on a large random sample of national populations. Also, there continue to be questions regarding the accuracy of these tests (technically, their sensitivity, or high true positive/low false negative rate, and specificity, or high true negative/low false positive rate).

There are some reports from China suggesting that a significant number of people have already had COVID19, in either a mild or asymptomatic form (“Latest Chinese Data Suggests Most Coronavirus Infections are Asymptomatic”, by Cindy Yu, The Spectator, 6Apr20.

In contrast, testing a random sample of 500 people in a Germany town found much lower levels of coronavirus exposure (“Blood Tests Show 14% of People are Now Immune to COVID19 in One Town in Germany”, Technology Review, 9Apr20).

Subsequent reports in two other locations show that an even lower percentage of the population has been exposed to coronavirus.
Based on studies of donated blood at a bloodbank in the Netherlands, the Netherlands Institute for Public health found that only three percent had COVID19 antibodies.

In “COVID-19 Antibody Seroprevalence in Santa Clara County, California”, Bendavid et al from Stanford tested a statistically representative sample of 3,300 people and found COVID19 in 2.81% of them (95% Confidence Interval of 2.24% to 3.37%). While this is 50 to 85 times more people than the number of cases that had been confirmed via testing, it is still quite a low percentage of the population.

This suggests that we will see repeating waves of coronavirus outbreaks in the future, that will continue until an effective vaccine is developed.

Beyond the future availability of serological tests themselves, there are very likely to be capacity constraints on laboratories’ ability to process them (see, “Swiss group says its machines can conduct 30m virus antibody tests this year”, FT 8Apr20. See also, “How Ready Is the US to Diagnose COVID19?” by BCG

Uncertainty: The extent of immunity acquired by people who have had COVID19

There are reports from China that about 33% of mild cases of COVID19 produce only very low levels of antibodies, which would limit protection against reinfection with the coronavirus (“Coronavirus: low antibody levels raise questions about reinfection risk”, by Stephen Chen, South China Morning Post, 7Apr20).

This seems consistent with another recent story from South Korea on apparent reinfection of patients who had COVID19 but were discharged after no longer testing positive for the virus (“Coronavirus reinfection fears grow as cured patients test positive with possibly ‘reactivated’ virus”, Fortune, 9Apr20).

These early indicators have yet to be confirmed in western nations through widespread serological (antibody) testing.

On the other hand, there is evidence that antibodies in people who survived the SARS virus provided some degree of immunity for up to two years (see, “Duration of Antibody Response after Severe Acute Respiratory Syndrome”, by Wu et al).

The good news is that the coronavirus that causes COVID19 appears to be mutating more slowly than influenza viruses do, which suggests that people who have had COVID19 may gain a measure of immunity that lasts longer than a year. However, the extent of immunity among recovered patients and the length of time they retain it still needs to be better estimated through additional research.

Uncertainties: Extent of seasonal reduction in coronavirus transmission with rising temperatures (and possibly humidity).

An initial hypothesis that warmer weather would lead to reduction in rates of coronavirus transmission rates appears to be contradicted by reports of its spread in warm, humid locations (e.g., “Ecuador’s Virus-Hit Guayaquil is Grim Warning for Region”, FT 5Apr20).

A recent flash report from the National Academy of Sciences was also pessimistic about the extent of seasonal transmission reduction we might see as average temperatures increase (“Rapid Expert Consultation on SARS-CoV-2 Survival in Relation to Temperature and Humidity and Potential for Seasonality for the COVID-19 Pandemic”).

Also, while the size of the samples is smaller than in the case of COVID19, neither SARS nor MERS displayed any seasonality in their rates of transmission.

Uncertainty: Deployment of largescale testing for active infections, along with widespread contact tracing and isolation.

In many nations, widespread deployment of testing (for active infections) continues to be constrained by multiple bottlenecks, from testing kits to testing locations to laboratory processing capacity. There are also uncertainties related to the sensitivity and specificity (i.e., accuracy) of these tests.

Uncertainty: Time to produce and scale up vaccination, and efficacy of those vaccines.

New vaccines typically take two to five years to develop. Given parallel development efforts and an expedited testing and approval process, current estimates are that will take 12 to 18 months for largescale deployment of a coronavirus vaccine.

However, beyond development, it is very likely that the rapid scale up of vaccine manufacturing will also be challenging (e.g., see, “Advances and Challenges in Vaccine Development and Manufacture”, by D’Amore and Yang, and “The Complexity and Cost of Vaccine Manufacturing 0—An Overview”, by Plotkin et al).

A secondary uncertainty is how long such a vaccine will be effective. Again, the good news is that coronaviruses have historically mutated at a much slower rate than influenza viruses, which implies a vaccine will be effective for a longer period of time.

If there is a silver lining to COVID19 it is that it will enable the world to be in a much stronger position to fight the next pandemic.

Until the arrival of COVID19, pandemic preparation efforts were focused on two variants of the influenza virus – H7N9 and H5N1 – which have the potential to be even deadlier than COVID19, when and if they acquire mutations that enable them to be much more transmissible.

See: CDC, “Summary of Influenza Risk Assessment Tool Results”; “The Pandemic Threat of Emerging H5 and H7 Avian Influenza Viruses”, by Troy Sutton; and “Global alert to avian influenza virus infection: From H5N1 to H7N9”, by Poovorawan et al

“Diabetes risk: what’s driving the global rise in obesity rates?”, by Chelsea Bruce-Lockhard in the FT

As if COVID19 wasn’t enough…

“The number of adults living with diabetes has reached an estimated 463m — equivalent to 9.3 per cent of the world’s adult population, and four times higher than the number of cases recorded four decades previously.

“The cost to the global economy is immense: upwards of $1.3tn, and rising. By 2045, the number of adult diabetes cases is expected to reach 700m.

“Behind this alarming increase lies a surge in obesity, which now affects nearly one third of the global population. According to the charity Diabetes UK, obesity accounts for 80-85 per cent of the risk of developing type-2 diabetes” …

“More than 55 per cent of the rise in adults’ weight over the past three decades has been driven by rural populations taking on habits more traditionally linked to urban-living. Just 13.5 per cent of the rise was caused by urbanization.”

“Are We Already Missing the Next Epidemic?”, by Joshua Epstein, on Politico.com

SURPRISE
“If political leaders are to contend with the disease sweeping the world, they must understand that it only looks like one contagion. In reality, it is two.

“One of them is the novel coronavirus itself, a new pathogen. The second contagion is ancient, more intractable, and more contagious: human fear.
“It’s not just a metaphor. Fear changes human behavior, for better and worse. As scientists and doctors fight the virus, the biggest challenge for government will become managing this second epidemic—the spread of fear and also its retreat, which can sometimes be even riskier…

“We need to think about the novel coronavirus as four separate epidemics: In addition to the disease it causes, Covid-19, there are also in epidemics of fear about the virus, fear about the economy—and likely soon—fear about a new vaccine. All four contagions are closely intertwined and will interact to amplify each other in complex ways.

“To get the world back on track requires controlling all four horsemen of the Covid-19 apocalypse—which makes the response far more complicated than leaders seem to appreciate” …

“Fear can actually be helpful: When people are afraid, they take urgent action like self-isolation and quarantines, which suppress the spread of infection. However, once the level of infection gets low, the fear evaporates and people come out of the basement: social distancing is lifted, quarantines end, schools and theaters reopen, transportation resumes. In a case like this, it is the decline of fear that wreaks havoc. If even a few infected cases are still at large, the resumption of business as usual simply pours gasoline—in the form of susceptible people—on to those infectious embers, and a second wave ignites. In 1918, exactly this behavioral story unfolded”…

“Given the steady growth of mistrust and misinformation surrounding vaccine safety in recent years, a Covid-19 vaccine—designed, tested and fielded under tremendous time pressures—is likely to be greeted with suspicion by many…Even a safe and effective vaccine will do no good if people refuse to take it…

"Everything turns on the relationship between the two fears, one of disease, the other of vaccine. In our model, if fear of disease exceeds fear of vaccine, then vaccine acceptance rises and the disease is suppressed. But if, at low disease prevalence, the fear of disease sinks below the fear of vaccine (as might happen when a disease recedes from our collective memory), people are more afraid of the vaccine than the disease. They eschew vaccine and a new disease cycle explodes.”

New information has emerged about why this coronavirus (COVID-19) is more transmissible than other coronaviruses like SARS and MERS.

SURPRISE
At the general level, viruses that originate in bats have some unique characteristics.

In “Corona Virus Raises Question: Why Are Bat Viruses So Deadly?” Robert Sanders from the University of California – Berkeley observes that, “It's no coincidence that some of the worst viral disease outbreaks in recent years—SARS, MERS, Ebola, Marburg and likely the newly arrived 2019-nCoV virus—originated in bats…

“Bats' fierce immune response to viruses could drive viruses to replicate faster, so that when they jump to mammals with average immune systems, such as humans, the viruses wreak deadly havoc.”

A recent article in the Daily Mail (“Coronavirus Could be 1,000 times more infectious than SARS”, 28Feb20) explained how this specifically relates to COVID-19.

“Experts initially presumed the spread of COVID-19 would follow the same trajectory as the SARS outbreak in 2002/3, because the viruses are almost identical genetically. But they have discovered the way it binds to cells in the human body is akin to far more aggressive diseases like HIV and Ebola.

“This makes it '100 to 1,000 times' more efficient at infecting people than SARS, according to researchers from Nankai University in Tianjin, northern China…

"SARS binds to a receptor protein called ACE2 after invading the human body through the mouth, nose or eyes. ACE2 does not exist in large quantities in healthy people, which helped limit the spread of the 2002 outbreak…

“Researchers looked at the genome sequence of COVID-19 and found a section of mutated genes that did not exist in SARS.

“Instead the coronavirus has 'cleavage sites' similar to those in HIV and Ebola, which carry viral proteins that are dormant and have to be 'cut' to be activated. HIV and Ebola target an enzyme called furin, which is responsible for cutting and activating these proteins when they enter the body. The viruses trick furin so it activates them and causes a 'direct fusion' between the virus and the human cells. COVID-19. binds to cells in a similar way, the scientists found.

“This finding suggests [the new coronavirus] may be significantly different from the SARS coronavirus in the infection pathway,' the scientists said in the paper. 'Compared to the SARS' way of entry, this binding method is '100 to 1,000 times' as efficient,' they wrote.”

“Temperature and Latitude Analysis to Predict Potential Spread and Seasonality for COVID-19”, by Sajadi et al

SURPRISE
Based on correlational data, rather than a causal understanding of the processes involved, the authors of this paper advance the hypothesis that high rates of COVID-19 transmissibility may be restricted to regions with relatively narrow temperature and humidity parameters, similar to other seasonal respiratory viruses like influenza.

Key COVID-19 Uncertainties at This Point

Last month we noted that given the available estimates for COVID-19’s Basic Reproduction Number (i.e., relative transmissibility) and Case Fatality Rate, the eventual severity of its impact would depend on the willingness and ability of western nations to implement steps like travel bans, quarantines, and other initiatives to limit social interactions in order to depress viral transmission rates.

Judging from what we have seen in Italy, imposition of these measures there and in other countries may have been too little and too late to avoid exponential growth in the number of infected people and in the short-run the overwhelming of health systems’ critical care capacity.

Going forward, there are still critical uncertainties to resolve in order to develop a more accurate estimate of COVID-19’s longer term impact. These include:
(1) the length and effectiveness of immunity to future infection conferred on those who have been infected and survived. If the immunity is strong and long-lasting, then the “herd immunity” hypothesis claims that the long-term impact will be minimal.

However, as we’ve seen in the case of influenza, herd immunity can be relatively weak when a virus evolves at a significant rate (actually, in the case of influenza the rate of evolution is variable). Put differently, the current pandemic will eventually damp down, but, like influenza, COVID-19 could become endemic, with seasonal peaks when temperature and humidity conditions are most favorable for its transmission (e.g., as was the case with polio before the development of the Salk vaccine in the late 1950s).

Hence (2), the second key uncertainty is the rate at which COVID-19 will evolve in the future.
In turn, this will have a substantial impact on the speed with which a COVID-19 vaccine will be developed, and its long-term effectiveness (e.g., witness the varying accuracy of annual forecasts of the composition of future influenza viruses, which drive targets for producing seasonal vaccines).

January saw the widespread outbreak of a new variant of the coronavirus in China, spreading from its epicenter in Wuhan.

SUPRRISE

There are two critical uncertainties to resolve with more evidence: (1) the transmissibility of the Wuhan strain, which so far appears to be high, and (2) the pathogenicity (CFR), which at this point still appears to be relatively low. And when you hear an estimated CFR, always remember to check the denominator on which it is based (lab confirmed or just symptomatic cases).

When it comes to contagious viral diseases, there is usually a tradeoff between their transmissibility (how easily they spread) and their pathogenicity (how many people who become infected die). Viruses that quickly kill their infected hosts effectively limit their own spread.

The number of infected people who die is measured by the "Case Fatality Rate." However, this is a noisy estimate, because the denominator can be based on lab confirmed cases (which increases CFR) or just symptomatic cases (which lowers estimated CFR).

Early estimates (based on very noisy reporting) have reported a preliminary CFR for the Wuhan strain of around 2%. However, this will likely change as more evidence becomes available.

To put Wuhan in perspective, the CFRs for Ebola and highly pathogenic H5N1 influenza are >60%. The 1918 pandemic flu was estimated at 10% to 20% (this strain was also relatively transmissible which is why it killed so many). The 2009 H1N1 "swine" flu CFR was estimated at 5% to 9%. By comparison, typical seasonal influenza has a CFR of one tenth of one percent or less (0.1%).
For other coronaviruses, SARS' CFR was estimated to be around 10%, while MERS' was 35%.

Transimissibility is measured using the “Basic Reproduction Number” (known as “R0” or “R-naught”), which is the number of people who will become infected by contact with one contagious person. If R is less than one (e.g., because of a high CFR), an epidemic will quickly “burn itself out”. In contrast, when R is greater than 1, a virus will spread exponentially.
Initial estimates of R for the Wuhan Novel Coronavirus are very noisy at this point. The World Health Organization has published a range of 1.4 to 2.5

For comparison, here are some historic estimated Basic Reproduction Numbers:
1918 Spanish Flu = 2.3 to 3.4 (95% confidence interval)
SARS Coronavirus = 1.9
1968 Flu = 1.80
2009 Swine Flu = 1.46
Seasonal Influenza = 1.28
MERS Coronavirus = <1.0
Highly Pathogenic H5N1 Influenza = .90
Ebola = .70

The most concerning finding about the Wuhan Coronavirus are claims that it may be capable of infecting other people before a patient becomes symptomatic (i.e., shows signs that he/she has contracted the virus).

SURPRISE

An article in the Lancet (“Nowcasting and Forecasting the Potential Domestic and International Spread of the 2019-nCoV Outbreak Originating in Wuhan, China”) found that, “Independent self-sustaining outbreaks in major cities globally could become inevitable because of substantial exportation of presymptomatic cases & the absence of large-scale public health interventions."

If it is supported by subsequent research, this initial finding will almost certainly lead to the imposition of more travel bans and quarantine measures in an attempt to limit transmission of the virus.

The Wuhan coronavirus will almost certainly depress global economic growth, but by an amount that is highly uncertain at this point.

SURPRISE

Global aggregate demand has already been weakening. A worsening slowdown (or growth turning negative) will very likely be reinforced by mounting debt servicing problems in our highly leveraged global economy.

Politically, failure to control the coronavirus could have substantial and highly uncertain effects in China, including, in one scenario, Xi Jinping’s loss of power.

SUPRRISE

In “Xi Jinping Faces China’s Chernobyl Moment "(FT, 10Jan20), Jamil Anderlini writes that, “Throughout Chinese history, the reign of an imperial line was believed to follow a pattern known as the dynastic cycle.

A strong, unifying leader establishes an empire that would rise, flourish but eventually decline, lose the “mandate of heaven” and be overthrown by the next dynasty...
“Similar to Europe’s “divine right of kings”, the mandate of heaven differed in that it did not unconditionally entitle an emperor to rule the Celestial Empire. While on the dragon throne, the “son of heaven” had total power over his subjects.

"But he did not have to be of noble birth and he could lose his heavenly mandate for being unworthy, unjust or plain incompetent. The right of the populace to rebel was implicitly guaranteed if the heavens were seen to be displeased. Natural disasters, famine, plague, invasion and even armed rebellion were all regarded as signs the mandate of heaven had been withdrawn”…

“The fact that China’s authoritarian system is particularly poor at dealing with public health emergencies that require timely, transparent and accurate information makes this far more significant than any other challenge Mr Xi has faced so far…

“Outspoken academics and intellectuals have braved imprisonment to lambast the Communist party’s failure of performance legitimacy. Some have explicitly referred to the mandate of heaven and pointed to numerous examples of late-stage dynastic decay.

"But the defining moment of this crisis — the moment when it went from being a serious challenge to a potentially existential problem for the party — was the death last Thursday of a 33-year-old Wuhan ophthalmologist called Li Wenliang.

“In the early days of the crisis, Dr Li had raised the alarm in online chat groups with his medical school classmates after witnessing numerous cases of a strange new pneumonia that did not respond to normal treatment. For that he was reprimanded by his hospital and summoned in the middle of the night by the police, who forced him and at least seven other doctors to sign confessions and pledges to cease spreading “rumours”.

“When Dr. Li contracted the disease himself, ordinary Chinese were outraged. Even the Supreme People’s Court in Beijing reprimanded the police and praised the doctors who first raised the alarm. But when Dr Li died on Friday the response was volcanic…

“Dr. Li’s story is so powerful in part because it fits neatly into another ancient archetype in Chinese history. The incorruptible Confucian scholar who speaks truth to the emperor but is persecuted, and ultimately dies for his honesty, holds a special place in China’s scholarly tradition. Dr. Li fits the role perfectly.

“Global, regional, and national sepsis incidence and mortality, 1990–2017: Analysis for the Global Burden of Disease Study”, by Rudd et al

SURPRISE

While the world focused on Wuhan, another very significant study was published, which found that deaths from sepsis infections are twice as high as previous estimates.

“In 2017, an estimated 48·9 million (95% uncertainty interval 38·9–62·9) incident cases of sepsis were recorded worldwide and 11·0 million (10·1–12·0) sepsis-related deaths were reported, representing 19·7% (18·2–21·4) of all global deaths.”

By comparison, the World Health Organization estimates that 9.6 million people around the world die each year from various cancers.

The escalating Ebola hemorrhagic fever outbreak in Democratic Republic of the Congo (current case count 1,600, which is increasing at an accelerating rate) amid a deteriorating local security situation). The case fatality rate is 63%.

Elsewhere, African Swine [hemorrhagic] Fever has been spreading rapidly in China, world’s largest pig producer. It is a highly contagious virus (between pigs) and has a very case fatality rate. Anytime a contagious deadly disease infects pigs, there is an elevated threat of a viral mutation or recombination that could lead to human infection (e.g., as in the case of strains of the influenza virus), because of the similarity of pig and human respiratory tracts.

Both of these situations remind us of the potential threat posed by infectious diseases and the substantial supply and demand side shocks they can cause. These wildcard risks are always out there, which makes early detection and accurate assessment of the threat they pose critical to avoiding the large downside losses they potentially can cause.

“Biodefense in the Age of Synthetic Biology”, by the US National Academy of Sciences

This new report provides more specific information on the nature of a developing threat.

“Synthetic biology expands what is possible in creating new weapons. It also expands the range of actors who could undertake such efforts and decreases the time required.”

“Based on this study’s analysis of the potential ways in which synthetic biology approaches and tools may be misused to cause harm, the following specific observations were made:

“Of the potential capabilities assessed, three currently warrant the most concern: (1) re-creating known pathogenic viruses, (2) making existing bacteria more dangerous, and (3) using microbes to make harmful biochemicals “

“With regard to pathogens, synthetic biology is expected to (1) expand the range of what could be produced, including making bacteria and viruses more harmful; (2) decrease the amount of time required to engineer such organisms; and (3) expand the range of actors who could undertake such efforts. The creation and manipulation of pathogens is facilitated by increasingly accessible technologies and starting materials, including DNA sequences in public databases. A wide range of pathogen characteristics could be explored as part of such efforts.”

“With regard to chemicals, biochemicals, and toxins, synthetic biology blurs the line between chemical and biological weapons. High-potency molecules that can be produced through simple genetic pathways are of greatest concern, because they could conceivably be developed with modest resources and organizational footprint.”

“It may be possible to use synthetic biology to modulate human physiology in novel ways. These ways include physiological changes that differ from the typical effects of known pathogens and chemical agents. Synthetic biology expands the landscape by potentially allowing the delivery of biochemical by a biological agent and by potentially allowing the engineering of the microbiome or immune system…Although unlikely today, these types of manipulations may become more feasible as knowledge of complex systems, such as the immune system and microbiome, grows.” [Note that this was written before the disclosure of the use of CRISPR technology in China to change human DNA to enhance resistance to smallpox].