With an RNA Virus, the Past Doesn’t Predict the Future

• Clinical trials focused on the efficacy of the Pfizer and Moderna mRNA vaccines after two doses as opposed to the J&J vaccine, which was studied as a one-dose vaccine
• A single dose of an mRNA vaccine offers much less protection than the single dose of the J&J vaccine
• Given the likelihood of future variants of the SARS-CoV-2 virus, we should focus on administering two doses of the mRNA vaccines, to ensure maximum effectiveness

Lately, the visual and print media has featured several prominent people – including leading epidemiologists – who believe that for the Pfizer and Moderna mRNA vaccines, a one-dose-for-more-people approach is the correct course of action to immunize individuals quickly and create vaccine-elicited immunity among the public. They acknowledge that a second dose should be given, but they don’t think that the timing of that second dose is as essential as one-dose partial protection. Some think it’s okay to have a lag time from the first dose to the second of two or three months rather than three or four weeks, as was done in the clinical trials and authorized by the FDA under the Emergency Use Authorization (EUA) last December. When numerous people with import and influence are saying the same thing, one assumes that the ideas shouldn’t be dismissed, and there are cogent reasons for the stance. So, let’s pause and unpack these ideas a bit.

Substantial data demonstrate partial efficacy after one dose of the Pfizer and Moderna vaccines. Data from the initial Pfizer trial showed that between day 12 and day 21 – between the first and second dose – there was a flattening in the incidence of COVID-19 acquisition in the vaccine versus placebo group with an efficacy of 52% (39 participants in the vaccine group acquired disease and 82 infections occurred in the placebo group). There are corroboratory data from Israel with efficacy data in the 50% range. The data in the Moderna trial were essentially the same. From randomization to dose two, there were 7 cases of infection in the vaccine group and 46 COVID-19 cases in the placebo group; so, on purely clinical grounds, the epidemiologist argues that more societal good could be derived by vaccinating two persons with 50% efficacy versus one person with 95% effectiveness. It poses an interesting decision to make on a personal level with respect to informed consent in telling someone they are giving up 95% after 3 or 4 weeks versus 50% efficacy until they get their next dose. Irrespective of the debate about this issue, I don’t think the real answer lies in a debate about the ethics of reduced efficacy from single-dose immunization or the efficiency of public health versus individual rights. The important thing to ask is, would we actually be doing more harm than good by administering one dose of the Pfizer or Moderna vaccine to more people?

Why do I suggest this?

I say that because the viruses we’re going to encounter today and what we will encounter in the next several months are not the same viruses that we tested the vaccines on and upon which the single-dose data are based; they are going to be more formidable adversaries. The variants that are emerging and taking over have higher infectivity and have learned to escape from neutralizing antibodies. We have learned that the seeding of that escape is among people with low/partial immune responses through natural infection, which means the virus has a greater opportunity inside the body to replicate. In this context, as weak immune responses occur, variants can mutate in the face of partial protection and this persistent replication can lead to prolonged viral shedding from the nose and mouth and subsequent community transmission. The infecting viruses are stressed but not eliminated by partial immunity. How do we overcome escape variants? We do so by using the full strength of the tools we have available to us. We provide immunity that is capable of eliminating the virus quickly and we don’t expose the virus to lots of people with low levels of immunity.

When we look at the protective antibody levels at day 21 after the first dose of the Pfizer vaccine, we see that the 50% serum neutralization titer is 29; 7 days after the second dose, it is 270 and 7 more days later, it’s 437! To offer a comparison, a level of 29 is equal to a low-dose convalescent plasma treatment, which has been associated with being a precursor for escape variants to emerge among immunosuppressed persons. The data with Moderna are similar: after one dose, the geometric mean titer of neutralization is only 18; 7 days after dose two, it’s 256; and 7 days after that, it’s 344.

The data we have on efficacy are derived from the clinical trials that were designed to match the vaccine strain with the original – or what some call “wild type” (Washington strain) – virus. We’ve recently seen the impact of the new variants on vaccine efficacy: the B.1.1.7 strain first identified in the UK required two- or three-fold more antibodies to neutralize; and the B.1.351 variant emerging from South Africa six- to ten-fold. It’s a pretty simple math equation to go from a titer of 20 after one dose of mRNA and come up with titers of less than 10 for the UK variant and neutralizing titers that “fall off the grid” for the B.1.351 strain (less than 5), which is essentially a titer that is not accurately measurable in any assay. This equation is very different after the second dose of mRNA vaccine, when a twofold reduction for 450 is 225 and even if one encounters the B 1.351 variant, it’s about a neutralizing titer of 1:75; 3.5 times the neutralizing levels above that seen with one dose.

Low antibody levels with one dose are magnified in the elderly, many of whom have titers less than 20; the elderly invariably require two doses to get a detectable neutralizing response. A similar situation is also seen among persons with a wide variety of chronic diseases: their less-than-robust immune response will have an even greater impact on levels of protection after one dose. Data on the origin of escape variants point to immunosuppressed patients and persons with untreated HIV as reservoirs for the selection of escape mutations, especially with the E484K mutation. My compatriots say if one dose works for Johnson & Johnson (J&J), why not do the same with Pfizer and Moderna? There is a difference: there is a much greater CD8+ T cell response in the J&J vaccine at one dose than with the mRNA vaccines after only one dose. It’s really a different mechanism of protection.

While my musings are inferential, I feel we will actually do more harm than good by markedly increasing the population of people with partial protective immunity.

I think it behooves us to solve the challenge of vaccinating our population by first immunizing with the regimens that we know have demonstrated high efficacy. Even with this approach, antibody titers will be stressed with the duration of time and the increase of circulating strains. Depending on the past is not how an RNA virus behaves. It uses the past to change its future in order to survive, so mitigating our best efforts is likely to be counterproductive. Good epidemiology does not necessarily mean good virology. This is one area where the past does not dictate the future. We need all the strength we can muster in the vaccine regimens. For the two mRNA vaccines, I want my friends and family to be immunized with the two-dose schedules as outlined in the FDA EUA-approved application.