The British HIV Association (BHIVA) recently updated its guidance on COVID vaccinations for people with HIV to align with the recommendation by the UK's Joint Committee on Vaccination and Immunisation (JCVI) that people aged 12 years and over who are immunosuppressed, including all people with HIV, should have a first or second booster dose six months after their last vaccine dose – even if they have already had a previous booster.
This booster should be of one of the two mRNA vaccines made by Pfizer or Moderna, even for people who originally had the Oxford/AstraZeneca vaccine.
Given that three doses were recommended as the original vaccine regimen for people with HIV and other clinically vulnerable people, and that some people with HIV have already had a booster dose this winter, the spring booster could be people’s third, fourth or even fifth COVID vaccine shot.
The efficacy of COVID vaccines in people with HIV
At BHIVA’s spring 2022 conference, immunologist Dr Dimitra Peppa of University College London outlined how our knowledge of the interaction between HIV and COVID-19 had developed over the last two years, and how this has influenced vaccine recommendations, including the latest one.
She said that we now knew enough to say that people with HIV in general did have a somewhat raised risk of developing severe COVID-19 disease if infected, and that their immune responses both to COVID vaccines, and to infection with the SARS-COV-2 virus that causes COVID, could be weaker than in other people.
However, the risk of disease and of poor response to vaccinations was mainly concentrated among people with low CD4 counts or unsuppressed viral loads.
Studies of vaccine efficacy show that the differences between people with and without HIV are significant, but not stark. In a meta-analysis of 23 SARS-COV-2 vaccination studies that included people with HIV, the magnitude of their antibody response was the same as that in people without HIV if they had a CD4 count over 500, but 15% less in those with a lower count. Pooled vaccine efficacy against SARS-COV-2 infection was 72% in people with CD4 counts over 450 but 59% in people with lower counts.
Similarly, in a Dutch study published just a month ago which compared immune responses to SARS-COV-2 vaccines in 1269 HIV positive and 440 HIV negative people, antibody responses to the Moderna, Pfizer and Oxford/AstraZeneca vaccines were 45-50% lower in the people with HIV than in the people without it.
However, a study of people with HIV who received the Oxford/AstraZeneca vaccine, published last year, found there was no difference in the magnitude or persistence of antibody responses in people with HIV versus people without HIV. And a follow-on study by the same team published six months later found that there had been a decline in both antibody and T-cell mediated immunity but that the decline had not been faster in people with HIV.
T-cell immunity is important because it is generally more durable than antibody-based immunity, and the vector vaccines such as the Oxford/AstraZeneca and Johnson and Johnson ones may stimulate a broader T-cell response than the mRNA vaccines. T-cell responses may also be less specific than antibody ones, so may preserve their potency against ‘variants of concern’ like Omicron that escape antibody-mediated immunity. Perhaps because of this, the Oxford team found a better T-cell response to vaccines among people who appeared to have immunity to other coronaviruses preceding SARS-CoV-2.
An interesting study from KwaZulu Natal in South Africa, where HIV prevalence is extremely high, looked at immune responses to SARS-CoV-2 infection in people with and without HIV. It found that people with HIV actually had a stronger CD8 T-cell response to SARS-CoV-2 infection than HIV negative people, and, in people with undetectable viral load on ART, milder COVID disease, possibly because of more, and more varied, prior exposure to other coronaviruses. However HIV-negative people had stronger antibody responses.
The crucial effect of very low CD4 count and severe immune suppression in general in impairing immune response to vaccines is becoming clearer. One December 2021 study from the US looked at the incidence of SARS-CoV-2 infection in people with and without HIV who received the Pfizer, Moderna or Johnson and Johnson vaccine. Seven months after vaccination, 2.1% of HIV-negative and 2.6% of HIV positive people had had ‘breakthrough’ infections. Incidence in people with CD4 counts below 350 was 3.4% and in people with a detectable viral load it was 3.3%.
A second study published the same month looked at SARS-CoV-2 infection after six months in vaccinated people with other causes of immune suppression, as well as people with HIV. The percentage of fully-vaccinated people who had a COVID infection at some point in the six months after vaccination was approximately 2.6%. But in people with HIV it was was 4.2% – similar to people who'd had bone marrow transplants – and in people who had had solid organ transplants, it was 7%. People with HIV were 33% more likely than average to get a breakthrough infection.
This study also showed that COVID variants influenced vaccine efficacy far more than HIV. Breakthrough infections became nearly 3.5 times more likely in the period after mid-June 2021, when the delta variant became dominant.
Posters at this month’s BHIVA conference highlighted by Dr Peppa (see references below) did tend to confirm that severe immune dysfunction impairs vaccine response. One (Ferrari et al) found that in 259 people with HIV, the magnitude of COVID vaccine T-cells responses in people with CD4 counts below 250 was only 5% as high as it was for people with higher CD4 counts.
Boosters: staying one step ahead of the COVID variants
But boosters help, even, or especially, for people with significantly impaired immune systems. Another poster at BHIVA (Vergori et al) looked at the vaccine response in 216 people with HIV who had been diagnosed very late, with a median CD4 nadir (lowest-ever count) of 46. All were now virally suppressed on antiretroviral therapy. After their third dose of one of the mRNA vaccines – a median of 4.7 months after their second dose – they had strong antibody responses regardless of their CD4 count.
A booster shot is needed to protect against the Omicron variant, in people with or without HIV. A study published in February found that an immune response that could neutralise the Omicron variant of SARS-CoV-2 was undetectable in people who had only received two or even three primary shots of a vaccine, regardless of HIV status. However if they were given a later booster of an mRNA vaccine (regardless of what their initial vaccine was) their antibody response changed into one that could neutralise Omicron. It wasn’t particularly strong – antibodies that could neutralise Omicron were 4-6 times more dilute than ones that could neutralise previous variants – but it was much more diverse.
Again, however, it is the T-cell responses to SARS-CoV-2 variants that may be more important than the antibody ones. In another study published in January, prior mRNA vaccination or prior COVID disease provided extensive immune coverage against Omicron. In fact mRNA vaccination provided even better coverage than prior infection, with effective CD4 and CD8 responses in 91% of recipients.
However, both of these studies were in the general population. Dr Peppa presented unpublished data from her group which compares the immune response to Omicron induced by a third booster shot of mRNA vaccine in people with HIV and in people without HIV.
This shows that people with HIV who have received a third booster shot have an immune response to Omicron that is similar to that seen in HIV negative people who have received only two shots, and isn’t much lower than the immune response seen to previous variants.
This work appears to confirm that people with HIV do tend to have a less robust immune response to SARS-CoV-2 vaccines than people without HIV. Interestingly though, it also finds that the immune response in people with HIV who have had three shots and who have had a prior COVID infection is much better. In fact, the immune response to Omicron seen in people with HIV who have had three shots and prior COVID infection is as potent as it is in HIV negative people who have not had previous infection or who have had previous infection but only two shots.
This begs the question: what if people with HIV are, as it were, “one shot behind” HIV negative people? Would four shots give them the same immunity against variants as three shots for HIV-negative people?
Because few people with HIV have had four shots yet, we don’t yet have much data, either in terms of number of recipients or follow-up time. But we do have some data from Israel, the first country to start giving people a fourth vaccine dose.
A paper published this month followed what happened to people in Israel “over 60 who were eligible” (which includes immunocompromised people) in the four to six weeks after they received their fourth dose. The number of cases of confirmed COVID infection was half what it was in the three-dose group four weeks after vaccination, though this protection waned in later weeks. However, protection against severe illness did not wane during the six weeks after receipt of the fourth dose, with people who received a fourth booster 3.5 times less likely to develop severe COVID disease than people who did not.
It was on the basis of this study and of the unpublished work of immunologists like Dr Peppa that the JCVI issued their new recommendation, which is supported by BHIVA.
What we still don’t know
Dr Peppa finished by saying that there was still much we had to learn. Both in people in general and especially in people with HIV, we did not yet know enough about how long effective vaccine responses last against the newer and more contagious variants of the SARS-COV-2 virus such as Omicron. There are no data to show which vaccine schedules might improve vaccine efficacy in people with HIV, especially in the deeply immunosuppressed. And the best strategy for boosting in people with HIV and people in general is still unclear.
Above all, of course, access to and takeup of vaccines for unvaccinated people is still unsatisfactory and has to be improved, especially in the low-income world.
Peppa D. COVID-19 immunity and vaccine efficacy in people living with HIV. COVID update session, BHIVA Spring Conference, Manchester, April 2022.
Ferrari L et al. How HIV modulates the safety and immunogenicity of the BNT162b2 COVID-19 vaccine. Poster abstract 290, BHIVA Spring Conference, Manchester, April 2022.
Vergori A et al. Immunogenicity to COVID-19 mRNA vaccine booster shot in PLWH by current CD4+ count. Poster abstract 293, BHIVA Spring Conference, Manchester, April 2022.