Feature Article: An Assessment of COVID-19 Vaccine Uncertainties and Probabilities
In terms of physical, economic, and mental health, a lot is riding on the world’s ability to develop and deploy and effective vaccine against the SARS-Cov-2 virus that causes COVID-19.
In this analysis, we attempt to answer two critical questions: How realistic are our current hopes? And what happens if they are dashed?
Implicit in our hopes are assumptions that five critical uncertainties will be favorably resolved over a given time horizon:
1) Development of a vaccine that stimulates the production of antibodies;
2) Ability to produce the vaccine in large volumes;
3) Ability to distribute large volumes of the vaccine to billions of people around the world;
4) Willingness of a large percent of the population to be inoculated with the vaccine;
5) The vaccine remaining effective for a long period of time.
In quantitative terms, the probability of a successful vaccine equals the joint (multiplicative) probability of that each of these sub-goals will be met. For example, putting a 95% probability on the achievement of each sub-goal by the end of 2021 means that the overall probability of vaccine success is just 77%.
Let’s look at the evidence in each of these areas.
Vaccine Development
As a general rule, it normally takes 15 to 20 years to develop a vaccine. In their “Clinical Success Rates, 2006-2015” study of the drug development process, the Biotechnology Innovation Association found that the overall “Likelihood of Success” (i.e., final approval and deployment) for 9,985 drug development processes studied was 9.6%. However, the LOA for drugs targeted at infectious diseases was 19.1%.
In a separate study published in 2018, Gouglas found that development of vaccines against epidemic infectious diseases has only a 6% chance of success (“Estimating the Cost of Vaccine Development Against Epidemic Infectious Disease”).
However, according to the Milken Institute (https://covid-19tracker.milkeninstitute.org/), there are now 211 vaccines for SARS-CoV-2 coronavirus under development. Applying a historical 6% success rate to this implies that this massively parallel and accelerated development effort will yield about 13 successful vaccines.
Conclusion: 99% estimated probability that a vaccine will be developed that generates an immune response with minimal side effects by the end of 2021.
Vaccine Production
On the surface, the outlook for mass production of successful vaccine candidates is encouraging. Manufacturers have announced capacity construction projects that they claim will be able to produce nine billion doses by the end of 2021.
Moreover, as the Congressional Research Service notes, obstacles related to vaccine manufacturers’ potential liability risks will likely be removed: “A COVID-19 vaccine is likely to be subject to specialized rules limiting legal liability under the Public Readiness and Emergency Preparedness (PREP) Act. To encourage the expeditious development and deployment of medical countermeasures, the Secretary of HHS has declared COVID-19 to be a public health emergency and invoked the PREP Act to limit liability for losses relating to the use of covered medical countermeasures during the public health emergency.
“Under HHS’s declaration, covered persons—including COVID-19 vaccine developers, manufacturers, distributors, and health care professionals who administer a vaccine—are generally immune from legal liability for losses relating to administration or use of an FDA-approved COVID-19 vaccine, except for willful misconduct resulting in death or serious physical injury. However, individuals who are injured or die as a result of receiving a COVID-19 vaccine may seek compensation through the Countermeasures Injury Compensation Program, a regulatory process administered by HHS” (“Legal Issues in COVID-19 Vaccine Development”).
However, in “Vaccines Use Bizarre Stuff. We Need a Supply Chain Now”, Kominers and Tabarrok highlight other production issues beyond manufacturing capacity. “Vaccine supply chains contain some unusual links, including horseshoe crab blood, shark liver oil and an enzyme that’s one of the world’s most expensive products. Other links rely on novel manufacturing processes that have not yet been implemented at scale. Each link in the chain needs to be stress-tested and strengthened. For the potential weak spots, alternative manufacturing processes need to be considered and prepared.”
In another story, “Without Vials and Needles, a Virus Vaccine Is Just a Formula”, Samanth Subramanian observes that, “In a whistleblower complaint, Rick Bright, then the director of the U.S. Biomedical Advanced Research and Development Authority (Barda), wrote that his agency had estimated as far back as January that the country would need from 650 million to 850 million needles and syringes for a Covid-19 vaccination drive. The Strategic National Stockpile held just 15 million at the time, and Bright kept hearing that other countries, aware that scientists were predicting a 12- to 18-month timeline for the release of a vaccine, were buying up stocks of syringes and needles from the U.S. Yet the American government didn’t place its first order for needles and syringes until May 1, he told Congress. When a vaccine is finally approved for manufacture, the rush to stock up on ancillary products will be unprecedented.”
Conclusion: 67% estimated probability that nine billion doses of a vaccine will produced by the end of 2021.
Vaccine Distribution
There are two big issues with vaccine distribution, one physical and one political.
Regarding the former, “Two-thirds of the world’s population is unlikely to have easy access to any Covid-19 vaccine that needs to be stored at freezing temperatures, the German logistics giant Deutsche Post DHL has warned.
“Research by DHL and consultancy firm McKinsey has found that insufficient “last mile cooling facilities in the final delivery stages and a lack of storage at clinics in large parts of Africa, Asia and South America would pose the biggest challenge to delivering a vaccine at scale. Existing “cold-chain” infrastructure, which allows for temperatures to be controlled throughout the delivery process, is only sufficient to bring a frozen vaccine to 2.5bn people in approximately 25 developed countries [or about 33% of the world’s population]” (“DHL Warns Of COVID-19 Vaccine Delivery Problems”, Financial Times).
On its website, UPS agreed, stating, “Let’s face a hard truth: Our pharmaceutical cold chains at this time do not have the equipment and scale to comprehensively deliver a temperature-sensitive vaccine for the COVID-19 pandemic.”
Moreover, even in the United States, a report by the Inspector General of the Department of Health and Human Services found the cold chain for vaccines was very fragile and resulted in vaccine spoilage (“Vaccines For Children Program: Vulnerabilities In Vaccine Management”).
Regarding political obstacles, RAND and others have noted that, with limited quantities of a vaccine initially available, there are abound to be conflicts over who receives it first.
“The US [and other countries] need an equitable distribution plan that reflects social realities. The vaccine should go first to health workers, essential workers, teachers, the elderly, and people whose living circumstances—from prisons to apartments—make it impossible to self-isolate if they get the disease. We need to ensure there is no discrimination, racial or otherwise, in the distribution process. And vaccinating teachers is particularly important because we cannot expect them to risk their lives to teach their students. There is broad agreement that keeping the schools closed will increase the gap between advantaged and disadvantaged children; a generation is at stake” (“It’s Going to be the Vaccine, Stupid!” by Brook and Rydzewski).
Conclusion: 67% estimated probability that the supply chain can deliver the vaccine to at least 5 billion people [67% of the world’s population] by the end of 2021.
Vaccine Acceptance
Herd immunity occurs when enough people in a community become immune to an infectious disease that it stops spreading. Traditionally, the herd immunity threshold has been estimated to be 60% of a population. However, recent research finds that it may be as low as 43% (“A Mathematical Model Reveals The Influence Of Population Heterogeneity On Herd Immunity To SARS-Cov-2”, by Britton et al).
Immunity can theoretically be acquired either by having had the disease (assuming a strong, prolonged, and effective immune response) or through vaccination (which makes the same underlying assumptions).
Seroprevalence tests by the US Centers for Disease Control and Prevention have estimated that, depending on location, between 1% and 7% of the US population has contracted COVID-19 (“Seroprevalence of Antibodies to SARS-CoV-2 in 10 Sites in the United States, March 23-May 12, 2020”, by Havers et al). That means that achieving herd immunity will require substantial takeup of new vaccines when they become available.
That raises a critical question: How enthusiastic will you be about taking a vaccine of as yet known long-term efficacy that has been developed in record time?
According to a Yahoo News/YouGov poll taken at the end of July, only 41% of US Adults said they would take the vaccine when it becomes available. 25% said they would not. The other 34% weren’t sure.
As Jonathan Ellen notes in “The Dangers of Herd Skepticism”, “substantial numbers of people already avoid routine immunizations. Most individuals who don’t accept vaccines such as routine childhood immunizations or the annual flu shot do so out of concern about side effects and doubts about effectiveness.
“Almost 15 percent of parents refuse recommended childhood vaccines, including the mumps-measles-rubella series, because of their belief in a link between vaccination and autism… In recent years, the percentage of U.S. residents 18 or older who reported receiving the annual flu vaccine was between 40 percent and 45 percent.
“Reasons for choosing not to receive the flu vaccine include a sense of invulnerability to the illness; belief that the vaccine isn’t effective; confidence in the body’s immune system to fight infection; concern that the vaccine will make one sick; and fear of neurological damage. An FDA-approved COVID-19 vaccine will present similar concerns.
“The FDA has set the standard for approval at an historically low level—the vaccine needs to protect only half of its recipients from infection over six months. In addition, when the vaccine is approved, the duration of its effectiveness will be unknown—will it require boosters or annual reformulations? Questions will also arise about side effects beyond the six to nine month period that participants in the trials were observed. Such realities could dampen enthusiasm for acceptance of the vaccine.”
Given the consequences of widespread resistance to voluntary vaccination, some are considering more coercive methods. In “An Overview of State and Federal Authority to Impose Vaccination Requirements”, the US Congressional Research Service wrote that, “Under the federalist system of the United States, state governments have the general authority, within constitutional limits, to enact laws ‘to provide for the public health, safety, and morals’ of the states’ inhabitants. In contrast to this general police power, as discussed below, Congress’s power to legislate is confined to those powers enumerated in the Constitution.
“The states’ general police power to promote public health and safety encompasses the authority to require mandatory vaccinations. Pursuant to this authority, states and localities have long enacted various compulsory vaccination laws for certain populations and circumstances, including for school children and certain health care workers and in cases of public health emergency. In the early part of the 20th Century, the Supreme Court twice considered constitutional challenges to such mandatory vaccination requirements. Each time, the Court rejected the challenges and recognized such laws to fall squarely within the states’ police power.”
The authors of the previously mentioned RAND study proposed a different approach: “We should consider whether and how to provide, at the time of vaccination, an electronic readable card confirming that the person had been vaccinated. We should also consider whether it is good policy—or even legal—to require employees, guests, students, or others to present a readable card proving they have been vaccinated if they want to work, fly, eat at a restaurant, study in a classroom, go to the opera, take a cruise ship, etc” (e.g., a vaccination based version of China’s Social Credit System).
In sum, it seems quite clear that vaccine acceptance is going to be an obstacle to achieving herd immunity.
Conclusion: 50% estimated probability that at least half the US population will be vaccinated by the end of 2021.
Vaccine Efficacy
Vaccines provide protection against infectious disease via two pathways. The first, “humoral response”, refers to a vaccine triggering the production of antibodies that directly attack a viral invader. The second, “cellular response”, refers to the enhancement of the body’s cell-level response (via T-Cells) to a viral infection.
Today, the extent to which a vaccine will trigger these responses, their efficacy in repelling infection, and the length of time they will persist all remain unknown.
Data about these responses in patients who have recovered from COVID-19 still vary widely.
The results of attempts to develop a vaccine for MERS (a coronavirus that is far more deadly than SARS-CoV-2 that was first identified in Saudi Arabia in 2012) are instructive.
According to The Gouglas paper cited above, 21 initiatives were undertaken to develop a MERS vaccine. Only four of them progressed to Phase 1 clinical studies. Of these, only one reported successful results (in 2016 by a team at Walter Reed US Army Medical Center).
In their paper, “Safety and Immunogenicity of an Anti-Middle East Respiratory Syndrome Coronavirus DNA Vaccine: A Phase 1, Open-Label, Single-Arm, Dose-Escalation Trial”, Modjarrad et al reported that, “This study showed that the GLS-5300 MERS coronavirus DNA vaccine was tolerable and immunogenic in humans. [Three doses of the] vaccine induced both antibody-based and cellular MERS coronavirus-specific immune responses.
"The study also compared vaccine-specific responses with those from individuals who had recovered from natural MERS coronavirus infections during a 2015 outbreak in Korea. The results showed that the immune responses generated in vaccinated study participants [over 12 months] were similar to convalescent responses after natural infection.”
However, the study could not test the extent to which the levels of immune system responses it found were sufficient to protect vaccinated patients against the disease, or for how long that protection would last.
Equally important, about one third of the patients in the study experienced mild or moderate side effects from the vaccine, including fatigue, head and body aches, and/or nausea.
Earlier this year, results from tests of a different MERS vaccine on animals reported that it did confer protection on them against deliberate exposure to MERS infection (“A Single Dose Of Chadox1 MERS Provides Broad Protective Immunity Against A Variety Of MERS-Cov Strains”, by van Doremalen et al). However this vaccine has not yet proceeded to human trials.
With respect to the efficacy of a SARS-CoV-2 vaccine, a final concern is the rate at which the virus will evolve in the future. A fast rate of evolution is what makes developing accurate vaccines against seasonal influenza so difficult. The consequence is that we have to get vaccinated once a year, and the degree of protection against infection that they provide varies from year to year.
Thus far, the rate at which SARS-CoV-2 has been evolving has been much slower than is the case for influenza, which, all else being equal, implies that a vaccine’s protection could last for a longer time (see, “On The Evolutionary Epidemiology Of SARS-Cov-2”, by Day et al). However, as noted in this month’s Evidence File, coinfection of patients with both SARS-CoV-2 and seasonal influenza virus could cause faster evolution in one or both of them.
Conclusion: 90% estimated probability that immune system response produced by the vaccine will protect people from infection by SARS-CoV-2 for at least one year.
Estimated Joint Probability of Overall Success by December 2021
To summarize, our estimates of successfully overcoming obstacles in five key areas are as follows:
• Vaccine Development = 99%
• Vaccine Production = 67%
• Vaccine Distribution = 67%
• Vaccine Acceptance = 50%
• Vaccine Efficacy = 95%
These estimates produce an overall joint probability of successful vaccine development and deployment by the end of 2021, and efficacy for one year thereafter of about 20% -- a one in five chance of meeting the overly optimistic expectations that almost certainly underlie many individuals’, companies’ and governments’ hopes today.
What Happens If Vaccine Hopes Are Dashed?
When unrealistic optimism gives way to more realistic expectations of how long it will take to develop and deploy a successful vaccine, there will almost certainly be another uncertainty shock to consumers, companies, and financial markets that will further slow the economic recovery.
It will also very likely trigger a sharp increase in mental health problems, which could produce hostile acts (e.g., violent protests) directed towards those perceived to be responsible should the critical failures be in vaccine production or deployment.
On the other hand, if the key failure lies in vaccine acceptance, protests will almost certainly be aimed at government authorities that try to compel vaccination (with some version of RAND’s vaccine “Social Credit System” likely to emerge as a compromise solution).
On the positive side, the United States learned to live with the threat of polio for many years until a vaccine was developed and deployed. The same will undoubtedly happen if the COVID vaccine falls short of its goals.
Besides continuing mandates regarding masks and social distancing, the most important initiative we expect to see is much greater focus on, and investment in, indoor air quality and associated HVAC systems, by both school districts and commercial property owners.