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February 3, 2021

Necessity of 2 Doses of the Pfizer and Moderna COVID-19 Vaccines

JAMA. 2021;325(9):898. doi:10.1001/jama.2021.1375

Two doses of the Pfizer and Moderna COVID-19 vaccines are necessary to confer adequate immunity.

The new vaccines for coronavirus disease 2019 (COVID-19) are highly effective, but controversy exists about whether a second dose should be delayed in order to immunize more people. The second dose is necessary and should be given.

How Do the COVID-19 Vaccines Work?

Messenger RNA (mRNA) is a highly unstable molecule that is used to create proteins in cells. mRNA can be synthesized in a laboratory and, when injected into cells, can cause pieces of proteins to be made. When these small pieces of protein (peptides) leave the cell, the body can develop an immune reaction to them. The 2 main vaccines in the US from Pfizer and Moderna use this approach to vaccinate people against COVID-19 infection.

Why Are 2 Vaccine Doses Needed?

When the vaccines were first tested, a relatively weak immune reaction was found within a few weeks after people received the first dose of vaccine, followed by a strong reaction when a second dose was given.

The next set of trials looked at the ability to prevent COVID-19 infection after receiving the 2 doses of vaccine. These vaccines were highly effective in preventing infections that cause symptoms after both the first and second doses. However, in these trials, a second dose was always given. It is not known how well the vaccine works if only 1 dose is given.

Controversy About the Need for a Second Vaccine Dose

Arguments have been made that because COVID-19 is such a serious disease that is rapidly spreading throughout the world and because vaccines can be made and delivered at a relatively slow rate, a first dose should be given and the second dose delayed until a large amount of the population receives the first dose.

It is known that the immune response to 1 dose of the vaccine is relatively weak, even though people who got their first dose had some protection against symptomatic COVID-19 infection. It is not known what will happen if people get only 1 dose.

It is possible that people who get only 1 dose will have only partial immunity to COVID-19 infection, resulting in a higher risk that vaccine-resistant variants of SARS-CoV-2, the virus that causes COVID-19, will develop. There is also concern that people who get only 1 dose will think they have sufficient protection against COVID-19 infection and not get a second dose. There is no evidence that people who get only 1 dose have adequate long-term protection against COVID-19 infection.

When Should the Second Dose Be Given?

The Centers for Disease Control and Prevention (CDC) recommends that the second dose of the COVID-19 vaccine be given within 3 weeks of the first dose for the Pfizer vaccine and within 4 weeks for the Moderna vaccine. No more than 6 weeks should lapse between doses, although if the second dose is not given during these time frames, it can be given without the need to repeat the first dose. It is not recommended to give the second dose any earlier than stated above, but if a person needs to get the second dose earlier, giving the second dose up to 4 days ahead of schedule is allowed.

Do the New SARS-CoV-2 Variants Affect Vaccine Efficacy?

So far, the new variants seem to increase the ability of COVID-19 to spread but do not influence how sick someone gets from the disease. The current vaccines appear to work against the new variants. When vaccines are created, they are designed to create many different antibodies to differing parts of the virus so that even if one part of the virus mutates, the antibodies may recognize another part of the virus. It is possible that there will be a variant that reduces vaccine efficacy, and the companies that make vaccines are creating new ones that should work against new strains of SARS-CoV-2.

Where to Get Vaccinated

COVID-19 vaccines are being distributed by governmental agencies. Your primary care clinician most likely does not have access to the vaccine. Check online for instructions for how the vaccine is being given in your area. Most states have instructions for how to get the vaccine that can be found on the CDC’s COVID-19 vaccine website (www.cdc.gov/coronavirus/2019-ncov/vaccines/index.html).

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Article Information

Published Online: February 3, 2021. doi:10.1001/jama.2021.1375

Conflict of Interest Disclosures: None reported.

Sources: Understanding the new SARS-CoV-2 mutation found in England. JAMA Clinical Reviews podcast. Published January 8, 2021.

COVID-19 vaccine safety—anaphylaxis and allergic reactions. JAMA Clinical Reviews podcast. Published January 6, 2021.

Lauring AS, Hodcroft EB. Genetic variants of SARS-CoV-2—what do they mean? JAMA. Published online January 6, 2021. doi:10.1001/jama.2020.27124

Coronavirus vaccine update with Paul Offit and Robert Wachter. Conversations with Dr Bauchner podcast. Published January 21, 2021.

5 Comments for this article
mRNA Vaccine Endpoints: Disease vs Infection
David Dassey, MD, MPH | Retired medical epidemiologist
This guidance states that the purpose of mRNA vaccines is to induce immunity to COVID-19 infection. Actually, the primary end point in both vaccine studies was to reduce clinical disease, not to prevent SARS-CoV-2 infection. Furthermore use of the phrase "COVID-19 infection," while commonly used by the media, is inaccurate since COVID-19 is a disease caused by infection with the novel virus SARS-CoV-2. As stated in the cited CDC reference: "The Advisory Committee on Immunization Practices (ACIP) has issued interim recommendations for the use of Pfizer-BioNTech and Moderna COVID-19 vaccines for the prevention of coronavirus disease 2019 (COVID-19) in the United States."

Both Pfizer/BNT and Moderna are continuing their research to determine if indeed these vaccines actually do prevent viral infection. If this is confirmed, there will be a much greater chance of rapidly reducing ongoing transmission by herd immunity and allowing relaxation of nonpharmaceutical prevention strategies. Until such time, all we can claim about these vaccines is that they both greatly reduce the incidence of serious and fatal infections, but not that they reduce infections per se.
Two vs Single Doses
Rashmi Patel, MD PhD | King's College London
While immunologically naive individuals will likely require two doses to stimulate longer-lasting immunological memory to SARS-CoV-2 following COVID-19 illness, this may not necessarily be the case for people who have already developed an antibody response to natural infection. A recent preprint suggested substantial and rapidly rising antibody titres following a single dose of a COVID-19 mRNA vaccine in people who were seropositive prior to vaccination, possibly due to an anamnestic response to already-established immunological memory [1]. It is worth considering this point in light of limited vaccine supplies.

1. Robust spike antibody responses and increased reactogenicity in seropositive individuals
after a single dose of SARS-CoV-2 mRNA vaccine. Florian Krammer, Komal Srivastava, the PARIS team, Viviana Simon. medRxiv 2021.01.29.21250653; doi: https://doi.org/10.1101/2021.01.29.21250653
Where Are Data on Secretory IgA?
Vin LoPresti, PhD Cell Biology | Retired Professor of BioScience, Former Senior Science Writer, Los Alamos National Lab
As some writers have noted, the lack of full transparency by Pfizer & Moderna means we are really discussing this topic only in the most general terms. More important is the question of what specific aspects of immunity are elicited by one-shot or two-shot mRNA vaccines. For example, do we see respectable IgG and IgA titers? With a vigorous secretory IgA (sIgA) response at mucosal surfaces, we might be feeling better about an individual's post-vaccination status because sIgA at those surfaces could diminish viral shedding, thereby reducing transmission to the remaining unvaccinated population. This could make that twice-vaccinated individual much less likely to shed residual virus afterward. This is an unresolved question, and pertinent data from the vaccine manufacturers should be demanded by government agencies.

Sure, memory immune responses most often do generate specific antibodies across the classes. And while it appears that both IgG and sIgA are present in individuals recovered from COVID, we can't simply assume that status for a novel method of injectable vaccine delivery (as we might for an oral or nasal vaccine as  second-dose). With the slow pace of distribution at only around 10% vaccinated, this is quite relevant to that 90-10 situation, and might not matter as much if we were up at 70–80% vaccinated. (There is, in fact, at least one developed oral vaccine, purportedly in Phase 1 trials.)

It's truly painful to watch this unfold as healthcare and government agencies simply accept the data crumbs that the manufacturers are willing to throw us rather than demanding complete Phase 3 trial data.
Efficacy of First Dose
Judy Mourant, PhD |
Table 15 of Moderna's briefing document says that 14 days after the first dose, vaccine efficacy is 92% (CI: 69% - 99%) (1).

What is the reference for the statement "a relatively weak immune reaction was found within a few weeks after people received the first dose of vaccine?" 


1. https://www.fda.gov/media/144434/download
Confounding two issues?
Gerald Silverberg, BA | UNU-MERIT and IIASA
This article seems to confound two unrelated issues: whether it is necessary to get a second dose of the Moderna and BioNTech/Pfizer vaccines, and whether extending the interval between doses is advisable now in order to inoculate more people in an emergency situation.

No one disputes that the former is true, but this says nothing about the latter issue. The present approved intervals, 3 weeks for bioNTech/Pfizer and 4 for Moderna, are what was used for the clinical trials but have never been shown to be optimal. The number of clinical trials to establish optimality would obviously be prohibitive.
For the AstraZeneca vaccine, extending to 12 weeks actually seems more efficacious.

The upside to extending the interval is obvious: appreciably more people can get at least a first dose. And first doses of the mRNA vaccines have been shown to provide >90% protection against disease and >80% against infection, and last for at least several weeks if not months. In the race against new variants of concern, this could be decisive.

What are the downsides of extending the interval? Marginally lower protection for the period of one dose. The possibility of promoting the emergence of new variants during the interval of partial protection. But completely unvaccinated individuals can also breed new variants, and in fact that's how the current generation of new variants emerged. So on balance this is an upside, not a downside.

In any event the two issues should not be confused.