The Vaccination Paradigm: Do the Naturally Immune Really Need a Second Dose?

Science, at a fundamental level, can be distilled into a series of paradigms, or sets of concepts and practices that define a scientific discipline at a particular period of time [1]. These paradigms are defined by the sum total of available scientific evidence.

Paradigms have guided scientific discovery for centuries. For example, the geocentric model of the universe, which posited that the Earth was the astronomical body that all other planets rotated about, held for more than 1,500 years. The miasma theory, which suggested that disease was caused by “bad air,” prevailed from the days of the ancient Chinese through the late 19th century.

These paradigms were shattered by the work of Copernicus and Galileo, John Snow and Louis Pasteur. We now know beyond a reasonable doubt that the sun is, in fact, the center of our universe and that disease is not caused by miasma, but by germs—bacteria, viruses, parasites, fungi, prions, and so on.

There is an essential lesson here. Science is not set in stone. As new evidence becomes available, whether assisted by the advent of new technologies or cutting-edge research, we scientists must evaluate our prevailing hypotheses, theories, and conclusions. We can’t be afraid to be proven wrong. By stubbornly clinging to our ideas, we do a great disservice to the scientific community and humankind at large.

The emergence of COVID-19 has accelerated the process by which we establish, challenge, and discard paradigms. Because of our more efficient technology and better understanding of the natural world, these paradigm shifts no longer take place over hundreds or thousands of years, but rather in months, weeks, or even days.

SARS-CoV-2 is a novel coronavirus and its emergence forced scientists to rapidly assess available information and evidence to guide public health policy. In essence, establishing a paradigm to guide scientific inquiry. We have subsequently critically evaluated many of these hypotheses and determined that they either required revision or removal from our constantly evolving paradigm of COVID-related knowledge.

Notable examples include the initial assumptions regarding SARS-CoV-2 transmission dynamics and mask wearing by the public. Through rigorous examination, we determined that fomites were not a significant factor contributing to the spread of SARS-CoV-2. Later, we found that SARS-CoV-2 was efficiently transmitted via the airborne route. Wearing masks was initially not recommended for those in the general public. However, as additional evidence emerged showing that masks effectively halted the transmission of the SARS-CoV-2 virus, all major health organizations switched their guidance.

The COVID-19 pandemic has brought the scientific process to the forefront of the public discourse. Scientists have been derided for altering COVID-19 guidance based on new evidence, accused of “flip-flopping” or deliberately deceiving the public. This is often compounded by the receipt of inconsistent information from the public health community. This is, however, merely a part of the scientific process. Before any paradigm change, evidence must be evaluated and challenged until a scientific consensus is reached. This does not happen overnight, but only after there is sufficient evidence to replace the prevailing paradigm.

We may have arrived at a similar paradigm shifting moment in the COVID-19 pandemic. Evidence has emerged showing that those who have previously been infected with SARS-CoV-2 may not require two doses of vaccine to be sufficiently immune. In this article, we will critically evaluate the available evidence and discuss whether we should shift our vaccination recommendations or vaccine-related paradigm.

THE ARGUMENT

COVID-19 was first identified in Wuhan province, China in December 2019. By March of 2020, the virus had spread to every corner of the globe. We all remember the fear and hysteria that swept through our communities. The lockdowns, the hoarding, hospitals overflowing, hundreds of thousands of deaths, millions of infections, severe economic hardship.

The announcement of highly safe and efficacious vaccines in late 2020 shocked the world. In under a year, we had sequenced the SARS-CoV-2 genome and developed and tested multiple vaccine candidates. The vaccine development effort is perhaps the biggest scientific and technological feat in human history. More importantly, for the first time in a long time, we had hope.

By early 2021, mass manufacturing and distribution of these vaccines was underway. There was significant debate in the scientific community and among policy makers on the vaccine administration strategy from the outset. The Biden administration’s view on COVID vaccination has been consistent and clear—everyone, regardless of previous infection, should receive either two doses of either the Moderna or Pfizer vaccines or a single dose of the Johnson and Johnson vaccine. However, there are those who argue that this position on vaccination is not reflective of the available evidence.

Some recent evidence has shown that natural immunity, which results from a COVID-19 infection, provides just as much protection against future infection as vaccine induced immunity, which results from immunization. There are several countries that have adapted vaccination guidance based on this emerging evidence. Since February, Israel has only required the previously infected to receive one mRNA dose of vaccine. Other countries, including Germany, France, and Italy among others have followed suit.

The potential implications of this research are significant. If natural immunity proves to be long-lasting and protective, the United States and other countries can prioritize vaccination in those who have not previously experienced infection by either restricting vaccination in the previously infected to a single dose or leaving them unvaccinated entirely.

These extra doses can then be distributed around the world, likely making vaccination possible months or even years earlier than expected for many. This strategy could help save thousands of lives and prevent newer, more infectious, and more deadly variants from emerging.

THE EVIDENCE

There have been several serological studies indicating that those previously infected with SARS-CoV-2 can receive sufficiently enhanced immunity after a single dose of mRNA vaccine [2-7]. These serosurveys compared antibody responses in two groups—the previously infected who received one dose of vaccine and the not previously infected who received two doses of vaccine. Both groups showed protective antibody responses. In the previously infected, a second dose showed little additional immunological benefit.

These serological studies, however, have several significant limitations. For one, most use small and/or convenience samples. Convenience samples are non-probability samples that are taken from groups of people that are easy to reach. These types of samples do not reflect the complex demographics of the population at large, meaning that we don’t have the ability to assess whether there are external factors that are impacting these results or if these results will be applicable in all populations. Serological studies are also unable to detect the real-world relationship between measured immunity and prevention of infection, disease, hospitalization, and death.

Large, generalizable, population-based studies were required to bolster the biological evidence. There have been three significant population-based studies that have emerged as a result.

The first, a CDC-led study of previously infected persons in Kentucky, found that among those that were previously infected, those that were unvaccinated had 2.34 times the odds of reinfection than those who were fully vaccinated [8]. Those that were previously infected and had one dose of an mRNA vaccine also experienced greater protection from reinfection than the unvaccinated, although this result wasn’t significant.

The second, a study of employees in the Cleveland Clinic, compared COVID-19 incidence in those who were unvaccinated and previously infected, vaccinated and previously infected, unvaccinated and not previously infected, and vaccinated and not previously infected. The incidence of COVID-19 was roughly equal between those who had either natural or induced immunity to SARS-CoV-2, but those that were unvaccinated and not previously infected experienced significantly higher incidence of COVID-19 [9].

The third, a large population-based study of Israeli citizens, examined the differences in SARS-CoV-2 infection, symptomatic disease, and COVID-19-related hospitalization and death between those who were unvaccinated and not previously infected, previously infected and had one dose of vaccine, and those that were fully vaccinated and had not been previously infected. This study found that natural immunity induced longer lasting and stronger protection against infection, symptomatic disease, and hospitalization compared to those who were fully vaccinated. More importantly, this study found that those who were previously infected gained additional benefit from a single dose of vaccine [10].

Each of these studies suffer individually from significant limitations. The CDC-led study does not use a large sample, for example. The Cleveland Clinic study population is composed entirely of healthcare workers, who undoubtedly have different risk behaviors than those in the general population. The Israeli study is retrospective, which is fundamentally problematic for outcome assessment. Testing for SARS-CoV-2 remains optional. This may lead to misclassification of persons included in the study. If for instance, those who were vaccinated were less likely to seek testing for mild symptoms, they would be incorrectly classified as non-reinfected although they did experience infection. Also, the Israeli study is a preprint, meaning that it has not yet undergone peer review. This means that other scientists have not yet had the opportunity to vet the study’s validity.

Prospective studies with rigid outcome assessment (COVID-19 infection, symptomatic disease, hospitalization, and death) are required. Nevertheless, the serologic and real-world studies paint a compelling picture. Based on available information, it appears that those who have been previously infected with COVID-19 do not need to undergo a full two-dose vaccination regimen.

THE IMPLICATIONS

There are limited and inconclusive data supporting the superiority of natural immunity compared to vaccine induced immunity. This does not, however, mean that we should shun vaccination and seek natural infection. COVID-19 is an incredibly dangerous disease, particularly as new, more severe variants have emerged. Vaccination provides a safe and effective way to prevent COVID-19 infection, hospitalization, and death.

Instead, these data indicate that if previously infected, a person does not currently need to undergo a two-shot series. A single dose of Pfizer, Moderna, or Johnson and Johnson vaccine combined with previous infection will provide sufficient levels of immunity to prevent the adverse effects of COVID-19. These second doses can instead be used to expand COVID-19 vaccination to countries and peoples around the world. Doing so can save millions of lives, prevent untold suffering, and limit the number of new and emerging variants.

We should, however, be prepared to adjust our views on vaccinations as more evidence becomes available. As we’ve discussed, science is an iterative process and must respond to evolving real-world circumstances. We cannot afford to rigidly fixate on a single hypothesis. We must adapt to the ever-changing landscape of the COVID pandemic. The refusal to do so will invariably result in unnecessary suffering and death.