The Science Is In: Our Immunocompromised Patients Need a Third Dose

Julie Tsu-Yu Wu, MD; Westyn Branch-Elliman, MD; Paul Monach, MD, PhD


July 30, 2021

Last Thursday, the CDC announced its support for third doses of COVID vaccine for our immunocompromised patients. However, these much-needed boosters cannot be given until the FDA gives its approval.

As physicians who care for patients with weakened immune systems, we are holding our breath and hoping the FDA will follow the science and wisdom of both the CDC and our overseas colleagues in France and Israel, and advocate use of these boosters. This critically important policy change would not only protect them but also society as a whole.

Immunocompromised patients — those with weakened immune systems that make them more susceptible to infections — comprise up to 5% of the US population. Almost everyone knows someone with cancer on chemotherapy, or with a chronic inflammatory disease such as rheumatoid arthritis. Patients with weakened immune systems face up to 10 times the risk of death from COVID-19, and we already know that the standard two-dose vaccine regimen isn't protecting them from having breakthrough infections.

Although we don't have data from randomized trials, there are a lot of other data supporting a booster dose strategy. Multiple studies have now demonstrated that cancer patients have variable and often delayed antibody responses to vaccination. Studies in patients with high levels of immunosuppression have also shown a substantial boost in antibody response following a third dose of COVID vaccine — a highly encouraging result for all immunocompromised patients.

Although measurement of antibodies is an imperfect surrogate assessment of immunity, it is likely that patients with high levels of antibodies are much better protected than patients with no or very low levels. We can also extrapolate from immune responses to other vaccines that the "extra booster" strategy is likely to be both safe and effective in this population. During the 2009 influenza season, rates of sufficient antibody production among cancer patients on immunosuppressive therapy increased almost twofold with an additional vaccine dose.

Advocating to protect immunocompromised patients is also a critical first step toward protecting everyone. As many of us feared, immunocompromised patients unfortunately can be laboratories for generating new coronavirus variants, and the national rise in cases driven by the more contagious Delta variant shows us how important it is to stop giving the virus chances to evolve.

Some might argue that we have other tools at our disposal and that doses of vaccines should be used in other ways. But the reality is that a booster vaccination strategy is more attractive than the other options. Vaccination is appealing as a prevention strategy partially because it is a limited time intervention that does not require day-to-day compliance or upkeep to maintain effectiveness. Universal masking and social distancing have been powerful tools for mitigating spread and may continue to be wise for many immunocompromised patients. However, indefinite compliance is impractical, sustainability is hard, and the benefit of masking really comes when it is universal and not just practiced by the most vulnerable. Infusions of protective antibodies in the event of getting COVID-19 are less effective than vaccination and may be cost-prohibitive and challenging to implement. Meanwhile, up to hundreds of millions of excess vaccine doses are available throughout the US, which is more than enough to cover extra doses for the immunocompromised.

Why not wait for more definitive, "gold standard" evidence? Following the science doesn't always mean waiting for definitive answers: We frequently act on the basis of intelligent reasoning and extrapolated data, especially when we know that an intervention is safer than the alternatives. This is why no one demands randomized clinical trials of parachutes. This strategy is also consistent with CDC pandemic policies: They prioritized immunocompromised patients for the first wave of vaccinations due to their increased risk for COVID-19 complications without waiting for further evidence of safety and efficacy in this population. We should use similar reasoning to begin booster vaccinations selectively.

Fast action in the face of pressing need has saved lives throughout medical history. In 2011, the FDA approved a novel approach to cancer treatment, called immunotherapy, for metastatic melanoma on the basis of immature but promising data. At the time, there were no good alternative therapies and average survival was 6-7 months. Now, melanoma patients on immunotherapy are living 5 years or more. The decision to move forward aggressively with early immunotherapy approval doubtless saved many. Likewise, we are now faced with a pressing need (COVID protection for immunocompromised patients) and a safe and well-tolerated intervention with incomplete but promising data (booster vaccination).

Like any area with limited data, there are, of course, multiple caveats. The optimal strategy for booster vaccinations may differ according to individual patient characteristics. A person who is immunocompromised from chemotherapy is not the same as one immunocompromised from solid organ transplantation. Their immune response to vaccination will differ, and booster vaccinations may not be effective — or even necessary — for everyone. Additional studies are needed to define populations most at risk and the optimal timing of a booster. However, these can happen concurrently with a recommendation for booster vaccination in patients with compromised immune systems. A national recommendation may also generate data that can be used to quickly answer these questions, without a need for a controlled clinical trial.

It is time for the FDA to act and to avoid the "wait and see" approach that has marked much of the pandemic. Our own research and studies from colleagues across the world keep coming to the same conclusion: Third doses for the immunocompromised increase immunity, thereby reducing their chances not only of becoming infected but also of spreading their infection to others. It's time to change course once again. We are sure it won't be the last time.

Julie Tsu-Yu Wu, MD, is a medical fellow in oncology at Stanford University. Westyn Branch-Elliman, MD, is an assistant professor of medicine at Harvard Medical School who specializes in infectious diseases. Paul Monach, MD, PhD, is a rheumatologist at Brigham & Women's Hospital.

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