Larry Corey, MD

The HIV pandemic, and COVID-19 pandemic, are intersecting.

The relationship between the two conditions is creating an epidemiological synergy that is starting to translate into additional misery for humankind.

If we can better understand this phenomenon, we can think more clearly about how to better protect the most vulnerable populations among us – people with HIV, and millions of others who are immunocompromised. We have seen overlapping epidemics before, and can draw from that experience.

Let’s start with HIV. Individuals living with HIV have a degree of immunosuppression which varies based on their therapy and disease course. If the disease course is well controlled and fully virologically suppressed on antiretroviral therapy, there is evidence to believe that these patients are at a normal risk of acquiring and controlling COVID-19, much like others in their families and communities.

This analogy is partially accurate in that those living with HIV can, because of their medicines, have obesity, diabetes, and increased lung disease, which are all predispositions or comorbidities associated with severe COVID-19.

Importantly, there are subsets of persons living with HIV, including those who are immune deficient with low T cell counts, those with viremia due to drug-resistant HIV viral strains, those not receiving or not taking antiretroviral therapy; and the many millions we know are living with undiagnosed HIV infection, including those recently infected.

These persons are subject to acquire persistent, prolonged COVID-19 infection, akin to organ transplant recipients and severely immunosuppressed cancer patients.  

There are many causes of immune deficiency, but in many countries, HIV infection is among the most common.

A recent case report by Karim et al. from South Africa, the country with the largest percentage of the population living with HIV of any country, described a case of HIV infection in a person who had very low CD4 counts due to resistant virus and a lack of compliance who developed COVID-19. Over a period of 200 days, this patient—who was ambulatory, living in the community, and without serious symptoms—shed COVID-19. The person had mild illness early on, which is why they were observed, and because of HIV, follow-up care ensued. The investigators had samples from the patient, and they shed COVID-19 at high titers, showing the development of multi-mutational changes in the virus over time. Mutational changes that essentially recapitulated the Beta variant, which has 9 to 11 different mutational changes from the original ancestral strain.

This is a single case, but it’s important because it illustrates a broader issue at work in our communities.

Individual patients living with HIV and compromised immune systems who have this prolonged shedding pattern can result in the kind of mutational changes that lead to germination and spread of variants of concern.

This case is illustrative because it’s not rare. Out of the estimated 38 million people living with HIV worldwide, South Africa alone has more than 16 million. In South Africa, that means one out of every four of its 65 million people are living with HIV.

So okay, the two epidemics are intertwined, what’s the concern? The concern is that these people will suffer more serious COVID-19 cases and that they may serve as the potential unwitting source of super-spreading events of new variants through household and community contacts.

As the greatest population of persons living with HIV is in sub-Saharan Africa, where vaccination rates are currently less than 2% of the populace, this continual reservoir of variant generation is and should be of concern to all of us. We need to recognize that we do not have a demonstrably effective vaccine against COVID-19 among persons living with HIV. People with immunocompromised profiles weren’t included in the well-controlled vaccine studies of the past year, when speed of enrollment was of the essence (see June 29 article in Timmerman Report).

While we lack comprehensive data, we have good reason to be concerned about vaccine efficacy in immunocompromised groups. The data that we have from the Novavax study in South Africa showed absolutely no efficacy against COVID-19. In the Ensemble Johnson & Johnson (J&J) study, too few cases were acquired to adequately evaluate the effectiveness of the one-dose J&J vaccine. And in the Moderna trial, no cases of COVID-19 were reported in the 150 HIV+ recipients who received vaccination. The reason for the lack of efficacy of the Novavax vaccine is puzzling and worrisome, as the post-vaccination binding antibody titers were well above natural infection and in the range associated with reasonable efficacy (median 33,000).

So, what’s going on here? The answer is, I don’t know the reason for lack of effectiveness, but I do know that the mRNA vaccines offer the most immediate solution to this major hole in the public health control of COVID-19 variants.

The data suggest that we need to take our most potent vaccines—mRNA or perhaps two doses of the J&J vaccine or a heterologous “mix-and-match” prime-and-boost with one of the vaccines being an mRNA vaccine—into areas of the world where there is HIV.

We need to urgently take steps to evaluate if our best vaccine regimens are able to effectively prevent acquisition of COVID-19 in all persons living with HIV, but especially among those with uncontrolled HIV.

This is the kind of urgent, heavy lifting that only the US government can do in an emergency.

The tale of these two intersecting epidemics needs a better ending than what we—as a global community—are currently creating. The Delta variant epidemic is rapidly illustrating that chasing variants is not a successful strategy. The Delta variant has swept through countries like the UK, Israel, and South Africa in four to eight weeks and is approaching the predominant variant in the United States at a speed that even with RNA technologies, we cannot keep up. Our approach must be to slow down the generation of these rapidly doubling super-spreading micro-epidemics of infection among unvaccinated persons.

The equation today among those unvaccinated individuals is not whether you will get COVID-19 infection but when you will get it. Slowing it down requires our best vaccine strategies. It’s certainly not too late. But we need both studies and implementation of our most potent vaccines and vaccine regimens to be applied to all of our immunosuppressed populations, the largest of which is HIV, for us to have a globally effective strategy.

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.

Larry Corey, MD

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

This is not a small group of people.

Estimates are that about 6.2 percent of adults ages 18-64 in the US 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 with biologic medicines that make people more vulnerable to infections.

Fifteen million people is a large community; people who live in all regions and every city in the US. They are your neighbors, your sister’s friend, the person next to you in line at the grocery store; people who are unlikely to mount strong immune response 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) and 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 I’ll discuss in a separate piece, are individuals living with HIV infection.

The global COVID-19 vaccine and prevention story, largely narrated by the 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 US.

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 in developing therapies and strategies to reduce infections in these people.

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 US adult population.

We knew that historically immunocompromised people are less likely to respond to vaccines than people with competent immune systems. There was also an issue how to discern vaccine side effects from side effects of all the medications immunosuppressed people take, and what other infections the immunocompromised person may have picked up coincidentally would have in relationship to the vaccine.

For this reason, including these patients in the initial efficacy trials would have 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, something we would not want in any person, let alone one who was immune compromised.

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 trials in these patient populations to the vaccine makers or other philanthropic or government entities to “pick up” and conduct.

While some trials were started, they have been small and limited in scope. Most importantly, none have been large enough to evaluate vaccine efficacy. Unfortunately, the current state of information 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 COVID-19 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 for immunocompromised people? Should we give them 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 first and if that doesn’t work, use long-acting monoclonal antibodies for those patients for whom 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 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 US, there are 16 million people living with cancer and at least 1 million organ/bone marrow transplant patients. These are real issues to many US and global citizens, their families, and communities.

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

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.