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Immunocompromised People Are Vulnerable to COVID-19. We Owe Them Some Answers.

The views and opinions expressed here are those of the authors and do not necessarily reflect the position of either Johns Hopkins University and Medicine or the University of Washington.

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Authors:
Larry Corey, Professor of Medicine
June 30, 2021
  • Immunosuppressed individuals may not mount strong immune responses to COVID-19 vaccines.
  • Because immunocompromised people were not included in the initial clinical trials, we have less knowledge about the efficacy of COVID-19 vaccines in these individuals.
  • We now face dual challenges: protecting these medically vulnerable individuals and also addressing their vulnerability to generate and to transmit SARS-CoV-2 and its variants.

As fully vaccinated citizens in our country and around the globe begin to dip their toes in the waters of a post-vaccination world, the following groups deserve greater consideration: immunosuppressed and immunocompromised people.

This is not a small number of people. Estimates are that about 6.2 percent of adults ages 18-64 in the U.S. are living with weakened immune function, along with about 2.6 percent of children, according to the Centers for Disease Control and Prevention. The prevalence of immunosuppression appears to be on the rise, as many people are living longer with cancer, HIV, organ transplants, or with chronic therapy that make people more vulnerable to infections.

These people live in communities all around the U.S. They are your neighbors, your sister’s friend, the person next to you in line at the grocery store.

We have about 15 million people in the U.S. in this immunosuppressed group who are unlikely to mount strong immune responses to COVID-19 vaccines. They need some extra help from all of us to stay safe.

So let’s talk about COVID-19 prevention strategies for this group of vulnerable people among us. Let’s start with patients who have received donor organs (like kidney or liver transplant recipients) or bone marrow transplants – who are on medications that suppress their immune systems to prevent graft rejection – as well as cancer patients whose immune systems have a reduced capacity to respond to vaccines because they’ve received chemotherapies that kill off many of their infection-fighting white blood cells. The second immunosuppressed population, which I plan to discuss in a separate piece, are individuals living with HIV infection. The global COVID-19 vaccine and prevention story, largely narrated by data generated from the USG COVID Vaccine (formerly Operation Warp Speed) program, did not include immunosuppressed persons in the clinical trials of the COVID-19 vaccines approved under Emergency Use Authorization in the U.S.

As the architect of these trials, I need to do some explaining here, especially because as a physician and scientist, I have spent almost all of my career working with immunosuppressed patients. When we started the clinical trials, we had no idea how effective these vaccines would be. Speed and efficiency in trial conduct were necessary. We needed vaccines for the majority of the U.S. adult population, and we needed them fast.

We knew that immunocompromised people, historically, are less likely to respond to vaccines than people with competent immune systems. There was also an issue with background noise. Because of all the medications immunosuppressed people take, it’s hard to tell if side effects of vaccines or monoclonal antibodies were caused by the new agent we were testing, or by other infections the immunocompromised person may have picked up coincidentally. For this reason, including these patients in the initial efficacy trials would have been problematic. It likely would have slowed down the trial and complicated the interpretation of side effects and hospitalizations.

Moreover, when we initiated the trials in summer 2020, we were concerned about the possibility of vaccine-induced COVID-19 disease enhancement. Fortunately, this is something we now know has not occurred in any of the vaccine trials.

Excluding immunosuppressed patients from the initial Phase III trials was the correct and necessary decision.

Unfortunately, however, we did not initiate concurrent parallel clinical trials in immunocompromised patients. That left this next round of trials for the vaccine makers or other philanthropic or government entities to “pick up” and conduct.

This lack of foresight has impaired our knowledge of the efficacy of COVID-19 vaccines among immunocompromised people. It brings us to the current state, in which the information we have on vaccination in organ transplant and cancer patients is an anecdotal collection of small studies showing that vaccines seem to be safe but, as predicted, elicit reduced levels of immune responses.

The data we have on organ transplant patients who have been treated with standard drugs that deplete B cells (e.g., Rituxan) and high-dose chemotherapy all tell us that at best 50% of persons develop detectable antibodies after two doses of mRNA vaccines. Having detectable antibodies is a good sign, but we have very sensitive tools that can detect very small concentrations of antibodies. Few of these patients are generating the kind of robust concentrations of neutralizing antibodies that immunocompetent persons are typically able to generate, and which are thought to be necessary to protect against moderate to severe COVID-19.

In many populations like these, where B cell depletion occurs, the percentage of persons with detectable levels of neutralizing antibodies is 20 to 25% at best. Little is known of memory T-cell responses in immunocompromised persons. This is an important area for further research, as T-cell responses could provide an important clue into whether the vaccines provide protection that lasts for the long term.

The main problem right now is that there are no data to indicate if the level of immunity reduces infection or, more importantly, if these immune responses are good enough to protect these individuals from hospitalization from severe COVID-19.

This is concerning because when immunosuppressed persons get infected with SARS-CoV-2, they frequently get prolonged, persistent infection. Case reports show patients with SARS-CoV-2 infection persisting for 200 days. During that time, the virus is replicating inside them, creating ample opportunity for variants to emerge. These variants often have the characteristic mutational changes associated with variants of concern. There is suggestive evidence that both the Alpha and Beta strains initially emanated from immunosuppressed patients.

Like COVID-19 in immunocompetent persons, the spectrum of illness in immunosuppressed patients is wide. The immunosuppressed patient can be asymptomatic – or mildly symptomatic – and transmit to family and friends and then introduce the variant into the community. Or they can have progressive longstanding pneumonia with prolonged shedding of the virus. Thus, we have a twofold difficulty. It’s not good that we can’t protect the most medically vulnerable from getting COVID-19, and if they do get infected, they are at risk of progressive pneumonia as well as transmitting these variants to their loved ones and communities.

SARS-CoV-2 as a pathogen shows no beneficence or mercy to the vulnerable.

So, we truly need to find solutions here. Can we develop a vaccination regimen that works? Should we give immunosuppressed individuals neutralizing antibodies for prevention, to give them some degree of temporary protection while we vaccinate as many people in the wider population as possible? What about giving them genetically engineered neutralizing antibodies, plus giving them a vaccine to help them mount their own immune response? How about trying vaccination or boosters first and if that doesn’t work, use long-acting monoclonals for those patients where vaccination has failed?

Vaccinating patients’ loved ones and households certainly is important. And hospitals that care for immunosuppressed persons need to make sure their employees are vaccinated to reduce variant spread.

Yes, in this author’s opinion, there should be mandatory vaccination for hospital employees.

These studies I’m proposing not only need to be about the immune responses to the vaccines as we’ve conducted in other studies, but also about studies of immunosuppressed persons globally where we can evaluate not only clinical efficacy but breakthrough shedding. Does vaccination eliminate the virus from the nose? If so, then how do new variants emerge? These studies will be a bit more onerous to run than the original Phase III trials, as we’ll need to collect nasal samples on a daily basis to answer this question about viral transmission from the nose. Today, we are we vaccinating cancer and organ transplant patients, but without any assurance that they are well protected. Do we know that two-dose inoculation will afford them the same amount of protection as the rest of their families and communities? The answer is no.

Can vaccinated immunocompromised persons, like the rest of the vaccinated population, take off their masks in most public spaces and move freely throughout their days with greater peace of mind? The answer is, we’re not sure.

These are all questions we need to answer for a population that is not trivial – either in significance or in number. In the U.S., there are 16 million people living with cancer and at least 1 million organ/bone marrow transplant patients. These are real issues to many U.S. and global citizens, their families, and communities.

We in the medical and scientific community owe them real answers.

Larry Corey, Professor of Medicine

Dr. Larry Corey is the leader of the COVID-19 Prevention Network (CoVPN ) Operations Center, which was formed by the National Institute of Allergy and Infectious Diseases at the U.S. National Institutes of Health to respond to the global pandemic and the Chair of the ACTIV COVID 19 Vaccine Clinical Trials Working Group. He is a Professor of Medicine and Virology at University of Washington and a Professor in the Vaccine and Infectious Disease Division and past President and Director of Fred Hutchinson Cancer Research Center.