With U.S. COVID-19 vaccination rates still below population immunity targets and the Delta SARS-CoV-2 variant sweeping the country, one group fears they may never get back to normal: the immunocompromised. Many immunocompromised people can safely get any of the 3 COVID-19 vaccines with emergency use authorization (EUA) in the U.S., as none of them contain live (or even whole) virus. But emerging data raise doubts about how effective these vaccines are in people whose immune systems are not fully functioning. After all, the concept of vaccination relies on provoking the immune system into a robust response against harmless versions of a pathogen, so that when the real threat comes along, the body is prepared. What happens when someone isn't capable of a robust immune response?

Who Is Immunocompromised?

The term 'immunocompromised' applies to a wide variety of conditions and treatments that impair immune system function. Conditions include primary immunodeficiencies present from birth, like severe combined immunodeficiency (SCID, also known as 'bubble boy' disease), as well as secondary immunodeficiencies resulting from HIV, diabetes and leukemia, to name a few. Patients can also become immunocompromised because of medical treatment. For example, transplant recipients, those with certain autoimmune diseases and cancer patients commonly take drugs either intended to suppress the immune system or that suppress the immune system as a side effect (e.g., chemotherapy and oral steroids).

Because the immunocompromised population is heterogeneous, people with some conditions or undergoing certain treatments may be better protected by COVID-19 vaccination than others. Part of untangling the efficacy of these vaccines in immunocompromised groups will be determining exactly who is protected, or not, and why.

Note that the remainder of this article focuses on studies pertaining to either the Moderna (mRNA-1273) or Pfizer-BioNTech (BNT162b2) mRNA SARS-CoV-2 vaccines, both for clarity and because these vaccines have the most data currently available.

How Does the Immune Response to COVID-19 Vaccines Differ in the Immunocompromised?

Studies of vaccines against other viral pathogens show that immunocompromised populations do not mount the same response to vaccination as non-compromised populations. COVID-19 mRNA vaccination of healthy individuals stimulates both humoral and cell-mediated immunity. That is, the body produces antibodies against the SARS-CoV-2 spike (S) protein, plus the B memory cells needed to reproduce antibodies in the future, as well as CD⁴⁺ type 1 helper T cells and CD⁸⁺ T cells specific to SARS-CoV-2 antigens.

Most studies available to date look at patients with secondary immunodeficiency and track antibody response to vaccination. These studies indicate that some types of immunocompromised patients do not mount as robust of an antibody response after COVID-19 vaccination as healthy patients. For example, only 25% of kidney transplant patients had detectable antibodies against the SARS-CoV-2's S protein after full mRNA vaccination. In a study that has not yet been peer reviewed, seropositivity rates (i.e., the number of people with detectable antibodies) for HIV patients (94%) were equivalent with healthy controls (98%), and more than 80% of those with autoimmune disease or solid tumors were also seropositive after vaccination. Those with hematologic cancers (e.g., leukemia and lymphoma) and solid organ transplant patients did not fare as well, with only 55% and 37% seropositivity, respectively. A study of more than 500 cancer patients mirrored these trends—those with solid tumors had a much higher rate of seropositivity (93%) than those with hematological cancers (66%).

Not surprisingly, treatment regimen for those who are immunocompromised due to medical treatment is another important variable. The preprint study on multiple types of immunocompromised patients also found a statistically significant correlation between steroid treatment (e.g., prednisone) and failure to mount a detectable antibody response post-vaccination.

Even in immunocompromised patients that have detectable antibodies after vaccination, titers are generally lower than in healthy patients. In a study of patients on immunosuppressive therapy for chronic inflammatory diseases, all patients were seropositive after vaccination, but antibody titers were significantly lower than in healthy controls.

There are fewer studies on cellular immunity in immunocompromised patients after vaccination. In a study of 45 kidney transplant patients, only 17.8% had detectable antibodies after mRNA vaccination, but 57.8% had SARS-CoV-2-specific T cells. The study of solid tumor and hematological cancer patients found similar rates of SARS-CoV-2-specific T cells among both groups after vaccination (45% and 46%, respectively), indicating that at least some hematological cancer patients who did not mount a detectable antibody response did mount a cellular immune response.

Data on those with primary immunodeficiencies is still scarce. Case reports of immune response to natural SARS-SoV-2 infection in those with primary immunodeficiency suggest that they can develop both humoral and cell-mediated immune responses to the virus. In addition, a small study of Israeli patients with primary immunodeficiencies found that 69% were seropositive and 73% mounted a SARS-CoV-2-specific T cell response after vaccination. These preliminary results suggest that those with primary immunodeficiencies do not necessarily respond more poorly to SARS-CoV-2 mRNA vaccination than those with secondary immunodeficiencies.

Does an Individual's Vaccine Immune Response Correlate With Protection?

Many groups are trying to find correlates of protection against SARS-CoV-2 infection by directly measuring the immune system's response to vaccination. These correlates are not only important in determining an individual's level of protection but can also be used as endpoints for future clinical trials, potentially saving time and money. Antibody titers (total or a subset, such as the neutralizing antibodies that specifically block viral entry into host cells) are a natural candidate. Not only do vaccine-induced antibody titers for other viral pathogens correlate with disease protection, but they are relatively easy to measure.

Data from rhesus macaques show that, in a dose-dependent manner, IgG antibodies protect against SARS-CoV-2 infection (as measured by replicating virus in broncheoalveolar lavage and nasal swabs) when transferred to immunologically naïve animals. In other words, serum IgG titers correlate with protection against both symptomatic and asymptomatic infection. Two recent studies, in Israeli healthcare workers and a preprint analysis of Coronavirus Efficacy (COVE) trial data that has not been peer reviewed, report correlation between neutralizing antibody titers after vaccination and likelihood of breakthrough infection. Thus far, the data indicate that those with high titers of neutralizing antibodies (a threshold that is still not well defined) are well-protected.

However, it is unclear if the circulating antibody levels reported in various immunocompromised populations constitute protection. Following other countries' leads, the U.S. Food and Drug Administration (FDA) is considering allowing booster shots in immunocompromised individuals. The hope is that a third exposure will increase overall seropositivity rates, as well as the antibody titers in those who are seropositive. A study published in the New England Journal of Medicine on transplant patients found that a third vaccine dose does boost seropositivity rate, as well as SARS-CoV-2-specific T cell counts, in this immunocompromised group.

Other studies in healthy individuals suggest that low or even undetectable antibody titers do not necessarily indicate vulnerability to infection, provided individuals have developed cellular immunity. Given that some immunocompromised patients who are seronegative after vaccination do develop SARS-CoV-2-specific T cells, it is possible that a greater percentage of immunocompromised patients are protected against COVID-19 than antibody data alone suggests.

The Bottom Line for Immunocompromised Individuals

The real efficacy test is still underway for all 3 COVID-19 vaccines authorized in the U.S.—how many fully vaccinated people become infected with SARS-CoV-2 under real-world conditions? Initial breakthrough infection data indicates that the vaccines provide a high level of protection against symptomatic COVID-19 and may provide sterilizing immunity (complete protection against SARS-CoV-2 infection, symptomatic or asymptomatic) for variants that were circulating in the U.S. in the first several months of 2021. But new data suggests that, while vaccines still provide a high level of protection against severe COVID-19, they do not always provide sterilizing immunity against the Delta variant or the Gamma variant.

These new data mean 2 things for those who are immunocompromised. First, if vaccine protection in immunocompromised patients is already lower than in the general population, protection against variants that escape vaccine-induced sterilizing immunity (which is mediated specifically by neutralizing antibodies) is likely even further reduced. Second, immunocompromised individuals may not be safe from infection even within highly vaccinated populations.

The ground is still shifting more than a year into the pandemic. Additional studies that look specifically at vaccine protection against symptomatic COVID-19 in immunocompromised patient populations are most likely to provide clear answers.

Keep up to date on COVID-19 research with ASM's curated COVID-19 Research Registry.