Boosters, third doses, and who needs them

Clinical Matters

Nothing is more contentious these days than the discussion surrounding additional doses of COVID-19 vaccines. Israel, having reached a high level of vaccination for its citizens, started offering boosters to its elderly population early on, followed by younger and younger age groups.

The US then went ahead and initially offered extra doses to immunocompromised individuals, specifically people who were immunosuppressed at levels equivalent to those of solid organ transplant recipients. In layman’s language, that means your immune system would have to be very weak to qualify.

A few weeks later, vaccination qualification criteria for boosters were modified to include those above 65 years old. In a contentious decision in which the Centers for Disease Control and Prevention (CDC) went against the recommendation of its own advisory council, the Advisory Committee on Immunization Practices (ACIP), the CDC recommended that boosters be also offered to people who were at high occupational risk. This disparity in opinion is a clear indication that the science behind boosters and third doses is far from settled.

To make matters even more complicated, many were confused by recent reports that the Strategic Advisory Group of Experts on Immunization (SAGE) of the World Health Organization (WHO) had recommended a third dose of Sinovac or Sinopharm for immunocompromised and elderly vaccine recipients. As of this writing, there is no final statement from SAGE, as these recommendations are expected to be formalized this November.

WHO clarified that the interim report from SAGE pertained to third doses of the COVID-19 vaccine, not boosters. The WHO stated further that the science for boosters remained inconclusive, and it was unclear whether homologous (same vaccine) or heterologous (different vaccine) boosters were equivalent, or one was better than the other. It also wasn’t specific to Chinese vaccines, rather all the current vaccines could benefit from a third dose for certain populations. Unless one is steeped in the science of vaccinology, these statements may sound like splitting hairs. Beneath these differences in terminology lie very important principles in immunology and healthcare equity.

When is it considered a third dose, and not a booster?

A third dose as part of a primary vaccine series acknowledges that two doses of a vaccine may not reliably induce durable immunity in the recipients. For instance, a primary series of hepatitis B includes doses at zero, one, and six months. Boosters may be given at later times for certain populations or occupations but are not required for the general population.

As more data emerge for COVID-19 vaccines, certain populations, namely immunocompromised and those older than 60, are less likely to get the same efficacy for two doses of COVID-19 vaccine compared with the general population. Therefore, the interim statement is to consider a third dose (not a booster) as part of the primary vaccine series. The timing of the third dose is still uncertain, but in the future, it might be given as early as 28 days from the second dose. A third dose will most likely be of the same (homologous) vaccine.

For the general population, it seems clear that two doses still continue to protect reliably against COVID-19. This may change as more long-term data emerge, but WHO, SAGE, CDC, and US FDA do not recommend a third dose for the general population at this time. Therefore, giving an extra dose to this population would be considered a booster and not a third dose.

Who needs a booster?

Boosting populations with occupational risk such as healthcare workers is highly contentious and very difficult to implement from a policy standpoint. While all COVID-19 vaccines reliably protect against severe disease for the general population beyond six months, there has been a clear decrease in clinical efficacy, i.e., preventing symptomatic disease. It is thought that a booster may increase antibodies enough to restore protection against clinical disease, especially in the healthcare workforce since they cannot afford to get even mildly ill and potentially infect their patients. While there is good data that both homologous and heterologous boosters increase antibody levels, it is unclear whether these higher antibody levels add any protection against variants of concern. There is a need for better studies for boosting since the benefit in terms of better clinical protection is unclear versus the risk of more side effects and depriving unvaccinated populations of scarce vaccines.

Recent data out of Israel seem to suggest boosting may indeed increase both clinical protection and severity of disease. Much of the gathered data, however, is within a few short weeks of the booster dose and may be confounded by the coincident increase in cases from Delta. Another recent randomized clinical trial with a third dose of Pfizer showed decreased clinical disease in those who got a booster versus placebo, but the data on whether there were differences in disease severity, hospitalization, or death has not been released. The mean time between the second and third dose in this trial was 11 months. It is these clinical outcome data that are under intense scrutiny since many public health experts and scientists are not convinced the data reflect a clear benefit of the booster dose. Nevertheless, the US FDA has recommended boosters for people 18 years old and above who have occupational risk or are at high risk for COVID-19. This will be difficult to implement since these criteria are not as clear-cut as age or the presence of specific comorbidities. In addition, the US FDA has stated that mixing vaccines, at least the ones available in the US (Janssen, Pfizer, Moderna) will be acceptable. The CDC and ACIP at the time of this writing have not yet weighed in on mixing vaccines but are expected to come up with guidelines for determining who specifically will qualify and the proper timing.

Equity of a third dose and boosters in areas of scarcity

While there aren’t any vaccine supply issues for Israel, the US, and Western Europe, the rest of the world continues to struggle with providing an adequate quantity of COVID-19 vaccines for the general population. Add third doses, boosters, and the upcoming vaccination of children and these policies are sure to exacerbate the global vaccine shortage. The WHO has called for a moratorium on boosters to at least the end of the year, but this appeal is unlikely to be followed by many countries who are anxious to start boosting their populations.

A third dose for elderly and immunocompromised populations does not bring up equity issues because if the primary series consists of three doses for them, then they aren’t considered fully vaccinated until they get the third dose. This justifies the diversion of a third dose from lower priority groups. Boosting, on the other hand, does raise equity issues, since there is not yet enough evidence of added protection for the target population. Boosting will divert vaccine supplies away from unvaccinated lower priority groups, who would clearly benefit from protection with a primary series.

When SAGE releases its final recommendation in November, it will likely recommend a third dose (second dose for Janssen) of the same vaccine for 60 years old and above as well as immunocompromised populations. Whether it will recommend boosters given the WHO statements on equity is unclear. Unless stronger supporting data becomes available, it is unlikely to recommend boosters for the general population. It is uncertain whether mixing vaccines will also be recommended, as the data that the US FDA is currently reviewing has not yet been publicly released. There are many studies ongoing that may provide better information in the next few weeks. Emergency Use Authorizations or EUAs will also need to be updated when those recommendations arrive. In the meantime, please do not mix or get a third dose or booster until there is a firm recommendation. It still isn’t certain whether these are safe or effective, and you may deprive someone of access to a vaccine that may save their life.