The recent announcement by the Biden Administration that fully COVID-19 vaccinated adults would be offered booster vaccine doses 8 months after their 2nd dose prompted a lot of thinking and my doing a lot of explaining about immunity and vaccines.
I wanted to think a little on paper to try to explain what immunity means, what to expect from a vaccine, and draw some conclusions regarding the impending booster program.
So, what is important about COVID-19 vaccines? Their most important aspect is their ability to prevent severe disease, hospitalization, and death. That is what they were designed to do, and they are doing it brilliantly with a combination of antibodies and T-cells. Indeed, the FDA authorization was based on the ability of the vaccines to stop disease (i.e. symptoms) not clinically silent infections. Hospitalized COVID patients are, for the most part, not vaccinated. There has not been waning of the ability of vaccines to prevent these outcomes (though the White House said it “could”) despite crude Israeli data that cannot be taken as evidence given the statistical paradox present.
The human system is very complex and hard to simply describe. We have innate (or ready-to-go non-specific immunity) and a more targeted specific type of immunity that takes time to develop called adaptive immunity. Adaptive immunity “adapts” or is directed towards specific pathogens. In broad strokes, there are two aspects to adaptive immunity: humoral (or antibody) mediated immunity and cell-mediated immunity. Both are very critical and work in concert. A major component of cell-mediated immunity are T-cells. There are various types of T-cells including T-cells that can kill infected cells, T-cells that orchestrate the operation of the immune system, and T-cells that dampen inflammation.
The most common evidence cited for the need for boosters is waning antibody levels. However, this is not – in and of itself – enough. First, we do not know what level of antibody (and the rarely accounted for T-cell immunity) is needed for immunity. We also do not have clinical evidence of true vaccine failure against important outcomes like hospitalization. There is non-peer reviewed data from Moderna showing higher efficacy with higher antibody titers but importantly, as the paper states, it is limited by the fact that efficacy against severe COVID was not assessed.
It is well known that antibody levels fall and then spring back up post-exposure (to the virus or the vaccine). That is how the immune system works – it is anamnestic. It “remembers” after the primary response and mounts a heightened response that staves off severe illness using both T-cells and antibodies in the secondary response. We fully expect antibodies to fall as time from exposure to vaccine or infection increases and we fully expect them to rise upon re-exposure. This isn’t vaccine failure; it’s just how the immune system works. That, infections in the vaccinated are generally mild is evidence of this process working.
When the CDC recommended a modification of the primary immunization series for the immunocompromised – which is distinct from a booster – it did so based on clinical evidence that amongst the relatively rare COVID hospitalizations of vaccinated individuals, the immunocompromised were overrepresented (~45% in a non-peer reviewed paper). Additionally, a study in solid organ transplant patientsrevealed not only did they, as expected based on experience with other vaccines, fail to mount a robust (or sometimes any) antibody response but had a 485X increased chance of COVID hospitalization versus someone without a transplant. That type of clinical evidence was then integrated with data on 3rd doses of mRNA vaccines increasing antibody levels in these populations.
With this booster recommendation to the public, none of that type of clinical data appears to be available for analysis. It is even unclear
Vaccines are not bug zappers; they are not forcefields. That breakthrough – the term itself falsely connotes vaccine failure – infections are mild is a vaccine success (even as they may increase in frequency). We must remember it is disease not clinically irrelevant infections we are targeting and that is done with 1st and 2nddoses, not 3rd’s. COVID is an endemic respiratory virus, it cannot be eliminated or eradicated. There is marginal utility in the general healthy population getting booster vaccinations at an 8-month interval. It is currently unclear that a 3rd dose will diminish the rare transmission risk posed by the fully vaccinated which prompted CDC guidance on masks to be modified. Granted, there is little harm but is chasing mild infections in the fully vaccinated an important task when a substantial proportion of the eligible population of this country does not even have one dose. Will this change the trajectory of the pandemic in the US or the world? Does putting 3rd doses in the arms of the heavily vaccinated change the situation in Mississippi?
There may come a time when boosters are needed and it’s important to be proactive and have streamlined approval and distribution pathways, but I don’t think that time is 8 months.