Today, December 10th, an experts’ commission on vaccines from the Food and Drug administration (FDA) is reviewing the scientific data of the Pfizer-BioNtech vaccine candidate to eventually determine whether it is safe and effective against the COV-Sars 2 virus that has been producing this terrible pandemic we have been suffering for almost a year. As expected, we are all very hopeful that they will approve it.
In a recent paper in Health Affairs, A. David Paltiel—nominated by President-elect Joe Biden to join a group of experts to advise him on the pandemic’ cure—et al. warn us that there are other factors that will determine the vaccines’ effectiveness. They said that: “Using a mathematical simulation of vaccination, we find that factors related to implementation will contribute more to the success of vaccination programs than a vaccine’s efficacy as determined in clinical trials. The benefits of a vaccine will decline substantially in the event of manufacturing or deployment delays, significant vaccine hesitancy, or greater epidemic severity.”
In a June 2020 paper, the FDA stated that there are two pillars of vaccine efficacy:
- Ability to cut the viral transmission. The capacity of the virus to jump from an infected person to a healthy one and provoke the disease.
- Disease-modifying effects. The capacity to slow the progression of the clinical symptoms and to hasten the recovery process to save scant resources.
A good vaccine will have direct effects—preventing the spread of the virus—and indirect effects—reducing the infectivity of affected individuals. The FDA determined that there should be a transmission endpoint and a disease-modification endpoint. “Regardless of how a manufacturer defined their efficacy endpoint, the FDA also established a minimum efficacy threshold, specifying a primary efficacy endpoint point estimate of at least 50% to ensure—in FDA’s view—that a widely deployed COVID-19 vaccine is effective.” The determination of that relatively low efficacy—common in vaccines against influenza, a much less contagious and deadly disease—baffled many scientists, used to much higher FDA demands for vaccines. However, the terrible human, social and economic consequences of this pandemic might have exerted a deciding influence on the experts, desperate for a good cure.
In order to rigorously evaluate the efficacy of a vaccine, the experts must not only determine their usefulness to cut the transmission of the virus but also its beneficial effects to stop the progression of the disease in already infected individuals. Moreover the vaccine efficacy against the virus is just one of many factors at play.
These authors used mathematical models because they “asked how vaccine-related changes in susceptibility to infection, progression of disease, and severity of illness might translate into population outcomes of interest such as cumulative infections, hospitalizations and deaths. We explored how those downstream outcomes might vary in the face of alternative operational assumptions (e.g. the pace of scale-up and the degree of public acceptance) and changes in the epidemiological context.” The researchers used three different scenarios, based on the Rt reproduction number:
- Rt of 1.5, which represents the strict adherence to preventive measures.
- Rt of 2.1, which represents greater risk due to the winter weather and greater indoor activity.
- Rt of 1.8, which represents a baseline.
The Rt is the ratio of the infected and the potential victim of transmission; an Rt of 2.I means that for each infected individual, he/she will infect two other individuals.
The researchers utilized the Susceptibility-Exposed-Infectious-Recovered (SEIR) model, which considers the disease progression as “a sequence of transitions among a finite number of health states (or compartments)” First they divided the “infected” compartment into four well defined sub-compartments like this:
- Asymptomatic
- Mild (outpatient)
- Severe (hospitalized)
- Critical (hospitalized in an ICU)
Second, they account for the vaccination by creating a parallel set of compartments:
- Susceptible unvaccinated
- Susceptible vaccinated
- Exposure
- Infection
- Recovery
- Death
They studied three types of vaccines:
- Preventive vaccine. It decreases the likelihood of infection in a healthy person
- Disease modifying vaccine. It improves the health outcomes in infected persons.
- Composite vaccine. It combines the attributes of both types of vaccines.
For both types of vaccines they set the efficacy rate at 50% for both components; they examined ranges of 25 to 75% in sensitivity analyses. The time needed to reach effectiveness were considered to be:
- Fourteen days for fast acting, single dose
- Thirty days in the base case in two-dose vaccines with partial immunity after the first dose.
- Forty-two days for a two dose-vaccine with no efficacy after the first dose.
The effectiveness of a vaccine deployment drive does not only depend on the quality of the product per se but also on two implementation variables: pace and coverage. The researchers said: “In a population of 100,000 and at a baseline Rt of 1.8, the model projects 61,112 infections and 2755 cumulative deaths over the course of 6 months without a vaccine. Introducing preventive, disease-modifying and composite vaccines at baseline efficacy levels would result in 42,583, 39,767 and 1,199 cumulative infections and 1,896, 1318 and 1199 cumulative deaths, respectively.”
They found that a 50% effective disease modifying vaccine would have a greater impact on hospital admissions, clinical morbidity, and mortality than a 50% effective preventive vaccine. The impact of both vaccines would be similar in the worst epidemics but the disease modifying vaccine would have a bigger benefit in less grave epidemics. The 50% effective composite vaccine would have the best impact.
The researchers found that the potential benefit of any vaccine is highly dependent on the number of circulating virus at the time of its introduction in a community. When the viral spread, measured by the Rt factor, is relatively low, a vaccine with relatively low efficacy—for example 25%—has greater benefits on the morbidity and mortality rates that a much effective vaccine—for example 75%—introduced when the viral spread is relatively high. Where a vaccine lands, has consequences.
This study buttresses the opinions of many health care experts who are warning the public at large that only an effective vaccination drive with a good product will not magically erase the human, social and economic consequences of the pandemic. We must still continue to use the Social Distancing guidelines for many months to come.
Note. On December 10, the experts’ panel of the FDA recommended the Pfizer BioNtech vaccine for human use. On December 14, the first American citizen, an Intensive Care nurse in a Long Island hospital, was the first patient to get vaccinated. On December 17, the FDA panel will review the results of the Moderna vaccine. Let’s pray for the best!
Stay distant. Stay safe. Stay beautiful.
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