This article was originally published on asm.org Dec. 22, 2020, but has since been updated by the authors.

In order to end this pandemic, we must end the spread of the virus. The misguided assumption that herd immunity could be accomplished by allowing life to return to normal has become a national catastrophe, resulting in a death toll of over 515,000 people and counting. The rational, scientific approach to end the pandemic is to develop protective vaccines that can be distributed globally. The rapid development of these vaccines, with only 11 months separating the publication of the first SARS-CoV-2 genomic sequence from widespread vaccine distribution, might be the most impressive scientific achievement in modern history.

With the U.S. Food and Drug Administration (FDA)’s emergency use authorization (EUA) of the Johnson & Johnson adenovirus viral vector SARS-CoV-2 (J&J) vaccine on Feb. 27, 2021, 3 COVID-19 vaccines are now being distributed in the United States. Distribution of the Pfizer vaccine began on Dec. 14, 2020, while distribution of the Moderna vaccine began the week of Dec. 21. As of March 4, 2021, 110 million doses of vaccine have been distributed, with 54 million (21%) of the adult population receiving 1 dose of either the Moderna or Pfizer vaccine and 28 million (11%)  adults fully vaccinated with 2 doses. This is woefully short of the roughly 200-250 million people that will need to be vaccinated to reach herd immunity, but is consistent with President Biden’s target of 150 million doses administered in the first 100 days of his administration. Based on Biden’s recent invocation of the Defense Production Act to speed manufacture of the J&J vaccine, he has promised that all U.S. adults who wish to be vaccinated against COVID-19 will be able to receive 1 of the 3 approved vaccines by the end of May.

The Unanswered Questions About COVID-19 Vaccines With EUAs

Although the vaccine development process has been a magnificent accomplishment thus far, humanity has never faced the task of vaccinating the global population in as brief a time as possible. Shortages in essential supplies, such as personal protective equipment (PPE) and testing reagents, are a continuing challenge during this pandemic. The mRNA vaccine technology used by Pfizer and Moderna has never been used at the scale that is needed. What manufacturing, distribution and administration problems will be encountered? Severe winter storms have slowed vaccine distribution and closed vaccination sites for days. More heartening has been the establishment of mass vaccination sites throughout the country where 1000s of vaccine doses are being delivered daily. Despite this, approximately 150-200 million more people need to be vaccinated for herd immunity, meaning 300-400 million doses of the Moderna/Pfizer vaccines or 150-200 million doses of the J&J vaccine. Will there be shortages of supplies needed for vaccine manufacture, such as vials to package the vaccine, shipping containers or dry ice necessary for maintaining cold chain during shipments or syringes?

Once vaccines safely arrive, the logistics of prioritizing vaccinations for each population, administering the vaccine and then tracking each individual to assure that they receive their second vaccine dose (if needed) at the right time, are unprecedented. Importantly, there will be a need to establish special protocols to administer these vaccines to individuals with a history of severe allergic reactions. What will the unintentional consequences on other vaccine programs be, if any? As we wait our turn to receive the vaccine, “patience” is the watchword.

Immunity following natural infection elicits both secretory IgA and IgG antibody response. Secretory IgA is central to providing mucosal immunity that prevents SARS-CoV-2 from initiating infection in the nasopharynx. Because all of the COVID-19 vaccines currently in clinical trials are given intramuscularly, they elicit an IgG response only. Although this response protects from lung and systemic infection, the vaccines may not provide sterilizing immunity in the upper respiratory tract. It is not yet known if any of the 3 vaccines actually prevent transmission. However, data from Israel, where 95% of the population has received at least one dose of the Pfizer vaccine and new case numbers have plummeted, suggest that this may be the case.

We do not yet know the durability of immunity provided by these 3 vaccines. We will learn more as the initial clinical trials proceed to their long-term, 2-year endpoints.

What will be the impact of the vaccines on pregnant women? Because a significant number of healthcare workers are women of child-bearing age and may be in the first trimester of pregnancy when they are vaccinated, we may begin to learn their impact on this initial vaccinated cohort. Observational studies, such as pregnancy registries, will be set up to monitor safety with EUA use of these 3 vaccines. The several dozen pregnancies and birth outcomes that occurred during the conduct of the Pfizer and Moderna Phase 3 trials are being followed closely.

The EUAs require careful observational safety surveillance on vaccinees by the 3 vaccine manufacturers. Clinical trials are ongoing for children 12-16 years of age for the Pfizer vaccine and those 12-18 years for the Moderna vaccine. A 2-dose trial of the J&J vaccine in adults, with doses given 2 months apart, is also ongoing.

How Do the 3 Vaccines Compare?

A common conversation in the community is, ‘which vaccine should I get?’ The simple answer is whichever is available to you most rapidly.

There has much discussion in the press about the differences in reported efficacy among the 3 vaccines. Comparing the different vaccines based on the efficacy reported from their clinical trials is not possible because the trials were done at different times, with different disease prevalence and with different geographic distribution of study sites. For example, J&J’s pivotal efficacy trial included sites in both Brazil and South Africa, where unique viral variants are common.

However, the key findings in all phase 3 trials of the 3 vaccines were that they prevented hospitalization, intensive care admission and death. The J&J vaccine has a clear logistical advantage. It requires only 1 dose, rather than 2, and is stored at refrigerator temperatures, rather than needing to be frozen. Since there is concern about vaccine accessibility, especially in medically underserved or remote populations, the J&J vaccine may facilitate access for these groups.

With the emergence of a variety of SARS-CoV-2 viral variants, there is concern about the emergence of escape mutants rendering the 3 current vaccines ineffective. All 3 vaccine platforms can be quickly modified to produce booster doses that target new variants; Moderna will start testing a booster against the B.1.351 variant soon. Both Pfizer and Moderna have also announced plans for clinical trials of boosters identical to their original vaccines, in the hopes that increasing antibody titers will fend off viral variants. Human trials of these boosters will be abbreviated, since only safety and immunogencity, but not efficacy, will need to be determined. In the meantime, vaccinating as many people as possible, as quickly as possible could prevent the emergence of additional variants that might escape the protective effect of the vaccines.

Vaccine Hesitancy and Risk

Although the EUAs for these 3 vaccines and those to follow offer great hope for developing vaccine-induced herd immunity and thus ending the pandemic, the development of herd immunity (estimated to occur when 70% of the population has immunity) is dependent on a large percentage of the population receiving an effective COVID-19 vaccine. In the U.S., vaccination rates for childhood illnesses are between 81-93%. As a result, most of these infections are rare and occur almost exclusively in non-vaccinated individuals. Currently, only 77% of Americans surveyed have either been vaccinated, are waiting to be vaccinated or are considering being vaccinated; 7% will be vaccinated only if it is required, while 15% will refuse to be vaccinated. The question is whether vaccinating 77% of a population where less than 10% have been infected naturally will result in herd immunity. The hope is that many who are now hesitant will agree to be vaccinated as we learn more about vaccine safety, especially the frequency of rare severe reactions.

All vaccines carry risks. Initial reports of anaphylactoid reactions in 2 health care workers in the U.K. made global news, but this was not entirely surprising based on their personal medical histories, which required them to carry Epipens due to severe allergies. It also was reported in the U.S that another individual without underlying allergies developed an anaphylactic reaction and required ICU admission. Because reactions are more severe with the second vaccine dose, worries about additional anaphylactoid or anaphylactic reactions are justified. However, these worries need to be put into perspective. The U.S. mortality rate of COVID-19 is currently 1.8%. By comparison, a small number of severe adverse reactions, estimated as 0.0002-0.0005% of doses administered, and no vaccine-related deaths have occurred in those receiving COVID-19 vaccines in the U.S. as of March 4, 2020. The benefit of receiving a COVID-19 vaccine so that lives will be saved, “long haul” COVID-19 cases with significant morbidity can be prevented, children can safely return to school, families can safely gather around the table and businesses large and small can safely reopen far exceeds the risk of serious vaccine complications.

Because rare, severe vaccine reactions have long been recognized, the U.S. has developed a safety net to compensate those injured by vaccines. To ensure that litigation costs stemming from severe vaccine-related injuries would not be a disincentive for both the development and manufacturing of childhood vaccines, the Vaccine Injury Compensation Program was established in 1986, funded by a nominal excise tax on each vaccine dose. Between 1988 and 2019, this program has provided those injured by vaccines with over $3.4 billion dollars. A similar program, the Countermeasures Injury Compensation Program, was established in 2010 to protect individuals who are injured by a vaccine, medicine or device to prevent or treat an agent causing a public health emergency. This program covers COVID-19 vaccines.

What Is Next?

Public health experts emphasize daily that public health measures are still essential in fighting this pandemic. It will take 6 weeks from dose 1 for each vaccinee in the initial Pfizer and Moderna vaccinated cohorts and 4 weeks for the J&J cohort after their single dose to develop peak immunity. Herd immunity, where more than 70% (and, hopefully 80 to 90%) of the population, is vaccinated, will not be here realistically until early summer. Between now and then, the prevention of tens of thousands of deaths still relies on us wearing a mask, social distancing and forgoing social gatherings, especially indoors. The recent decision to re-open the Texas economy, which represents 9% of the U.S. population, without any restriction, at a time when cases have increased there over the past 2 weeks from a 7-day average of 4,500 cases/day to 7,600 cases/day, is cause for concern. We are all tired of this, but just imagine how tired the ICU nurses are who have had to watch so many loved ones die without family near. What about our exhausted medical laboratory and public health professionals who are near the breaking point due to never-ending laboratory testing? You owe it to all healthcare professionals and you owe it to yourselves to follow public health guidelines, and when it is your turn, roll up your sleeve to be vaccinated.

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