Fleets of delivery trucks leaving warehouses to distribute the first Covid-19 vaccine doses across the country in late December 2020 sent a reassuring message to Americans across the country: Access to highly safe and effective vaccines will help us end the pandemic.
Within days, health care workers and thousands of individuals at highest risk of exposure to or complications of Covid-19 were rolling up their sleeves, grateful to be getting vaccinated.
But the resilience and shape-shifting of SARS-CoV-2, the virus that causes Covid-19, has tempered that early enthusiasm. Vaccine and public health experts have learned that the effectiveness of Covid vaccines sometimes depends on the recipient. This is especially true for people who are immunocompromised, who may need more than vaccines to help them prevent or fight this potentially deadly infection. For many of these individuals, it still feels like the early days of the pandemic, when everyone felt vulnerable to the virus.
There are two main groups of people living with compromised immune systems. Some people are born with immune deficiencies (called primary immunodeficiency). The majority acquire this problem (called secondary immunodeficiency) during life. HIV infection or some cancers can cause it, as can treatments to prevent rejection in organ transplant recipients or to manage conditions such as cancer, multiple sclerosis, or rheumatoid arthritis.
An estimated 7 million Americans are immunocompromised, rendering them especially vulnerable to the worst effects of Covid-19 because the vaccines don’t always trigger a sufficiently protective immune response in them.
The CDC recommends that all immunocompromised individuals receive extra vaccine doses. Those who received the standard two doses of an mRNA vaccine (Pfizer/BioNTech or Moderna) should get a third dose 28 days after the second one and, as the CDC announced on Friday, an additional booster dose after three months (but not sooner). In many cases, the additional dose adds to the protection these vaccines afford. For those who received the one-dose Johnson and Johnson vaccine, the CDC recommends they get an mRNA booster and a third dose. (Though anyone who missed the recommended window periods should still go ahead and get the additional vaccine dose — there are no reasons to think “It’s now too late.”)
Although the recommendations are simple, many retail pharmacies aren’t up to speed on the latest recommendations and there have been reports of people being refused the additional dose. As a result, the CDC made an additional announcement on Feb. 4 in an effort to provide greater clarity and increase awareness.
But even with the panoply of vaccine doses, the varied causes of immunodeficiency mean that different people respond quite differently to vaccination. Even healthy people vary widely in this regard: In clinical trials of the vaccines (which excluded immunocompromised people), there were up to 50-fold ranges in the levels of antibodies formed (known as antibody titers).
Given the number of variables, there is no simple way to tell in advance how strongly an immunocompromised individual will respond to vaccination. The general rule of thumb is relatively poorly — and some don’t benefit at all.
For example, rituximab, a drug often used to treat certain types of lymphoma, rheumatoid arthritis, and other less-common inflammatory diseases, inhibits — by design — antibody-producing cells. Most people taking rituximab can’t make antibodies to the Covid-19 vaccines, and the effect of this drug can last for months. A third dose, and even a fourth, is unlikely to help them much. That said, vaccination is still important for many people taking immunosuppressive drugs because the vaccines may still be able to activate some components of the immune that help protect against serious Covid-19.
In fact, “more is better” might not be the right approach for every immunocompromised individual. In some cases, the extent or nature of the immunocompromising condition is so severe that additional vaccine doses simply can’t help. Too frequent vaccinations could be associated with an increased risk of adverse reactions, which can be serious in people who are, by definition, already dealing with significant health problems. And it isn’t solidly known how multiple and frequent vaccine doses might interact with the various components of the immune system, especially in people who already have mounting antibody and/or T-cell responses.
One way to help this group of people would be to prioritize the use of available monoclonal antibodies (MAbs) to protect them from infection and/or developing severe Covid-19. and to fast-track clinical trials and emergency use authorizations for next-generation MAbs.
The FDA has authorized several monoclonal antibodies to treat Covid-19. The first were products from Regeneron (REGEN-COV: casirivimab and imdevimab) and Eli Lilly (bamlanivimab with etesevimab). They were followed by entries from GSK/Vir (Xevudy: sotrovimab), AstraZeneca (Evusheld: tixagevimab with cilgavimab), and just last week Eli Lilly (bebtelovimab).
When antibody therapy is begun a few days after symptoms appear, it can reduce the severity of Covid-19. Xevudy appears to retain its activity against the Omicron variant, while the REGEN-COV and bamlanivimab plus etesevimab monoclonals do not, which has led FDA to limit their use only for patients likely to have been infected with or exposed to a variant that is susceptible to these treatments.
It is also possible to give monoclonal antibodies to uninfected, at-risk people with the goal of protecting them from acquiring the virus. Using monoclonal antibodies this way is called passive immunization, since protective antibodies are delivered “passively” (by intramuscular injection at regular intervals) rather than actively inducing the body to produce them in response to a vaccine.
Only one monoclonal antibody product, Evusheld, is now authorized for prophylactic use in high-risk individuals. Like Xevudy, it is active against the Omicron variant. It is a practical option because it needs to be given only every six months, but it is in short supply.
Clinical trials have shown that passive immunization helps prevent Covid-19, and it has a good track record against other infections like respiratory syncytial virus.
Authorizing the use of monoclonal antibodies to prevent Covid-19 infection has moved slowly. There’s now a clear and urgent need to accelerate the evaluation and authorization of additional potent and broadly active monoclonal antibodies that can be used to prevent infection with SARS-CoV-2.
Until then, greater and more timely access to effective Covid-19 drugs such as the oral antivirals Paxlovid or molnupiravir, or the intravenous antiviral remdesivir, would help immunocompromised people survive if they do become infected. These drugs work best when given very early after infection, a time when people may feel relatively well and be unaware they might need medical care. Public health authorities need to improve communication with immunocompromised people to alert them of the importance of getting tested and seeking medical advice as soon as they develop symptoms, even if they are only mild.
Immunocompromised people are a medically vulnerable group. Protecting them should be a public health priority, as many are already dealing with life-threatening medical conditions. We don’t want to see them have to cope with Covid-19, too.
Life can’t go back to normal until everyone has effective tools to cope with Covid-19.
Luciana Borio is an infectious disease physician, a senior fellow for global health at the Council on Foreign Relations, and former director for medical and biodefense preparedness policy at the National Security Council. John P. Moore is a professor of microbiology and immunology at Weill Cornell Medicine in New York City. The authors have no links to any companies producing or evaluating any of the therapies mentioned in this article, and declare no conflicts of interest.
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