The COVID-19 pandemic has forced rapid changes in vaccination strategies to combat emerging variants and overcome the waning immunity observed after early vaccine doses. Our study set out to explore how an mRNA booster – specifically one that combines the ancestral strain with the BA.4/5 variant – could enhance immune responses in people living with HIV (PLWH). In this post, we offer an inside look at our study’s motivation, challenges, key findings, and the potential impact on future vaccination approaches for vulnerable populations.

Motivation and research questions

PLWH, even when treated effectively with antiretroviral therapy (ART), often display immune alterations that can affect the magnitude and durability of vaccine-induced responses. While early COVID-19 vaccines demonstrated robust immunogenicity in PLWH (with exceptions for those with uncontrolled viraemia or severe immunodeficiency), the evolution of SARS-CoV-2 into immune-escaping variants like BA.4/5 necessitated a re-evaluation of booster strategies.

Our central research question was:

Does the original–BA.4/5 bivalent booster induce a durable and variant-specific immune response in PLWH?

To answer this, we compared the immune responses of PLWH receiving the bivalent booster to those receiving a monovalent booster, and also to a control group of HIV-negative healthcare workers (HCWs) who received the bivalent booster.

Study design and methodology

We conducted a prospective longitudinal study involving three groups:

• PLWH receiving the original–BA.4/5 bivalent booster as their fourth vaccine dose,
• PLWH receiving an original monovalent booster,
• HIV-negative HCWs receiving the bivalent booster.

Blood samples were collected at three time points: before vaccination (T0), one month after the booster (T1), and between 4 and 9 months after the booster (T2). This timeline allowed us to capture the immediate peak of the immune response as well as the subsequent decline over time.

Our analyses focused on both cellular and humoral immunity. We measured SARS-CoV-2–specific T cells (including polyfunctional CD4 and CD8 T cells that produce multiple cytokines such as IFN-γ, TNF-α, and IL-2) and B cells, as well as humoral responses via RBD-binding and RBD-blocking antibodies, these last being a proxy of antibody neutralising activity.

Key findings: a dual-edged immune response

Our study revealed several notable findings regarding the immune response to the original–BA.4/5 bivalent booster in PLWH:

Humoral immunity

• Antibody response: Following the booster, there was a significant increase in both RBD-binding and RBD-blocking antibodies against the ancestral strain and BA.4/5 in PLWH, similarly as observed in HIV-negative HCWs. However, these elevated antibody levels were transient. By T2, the antibody titres had largely returned to pre-booster levels.
• Immunologic imprinting effect: Despite the enhancement of BA.4/5–specific responses, the immune system still showed a preference for the ancestral strain, a sign of immunologic imprinting. However, a comparison between the two booster types revealed that the monovalent booster primarily increased antibodies against the ancestral strain, while the bivalent booster was more effective in expanding BA.4/5–specific RBD-blocking antibodies, a promising sign for variant-adapted vaccines.
• Impact of HIV-related T cell dysfunction: Importantly, our analysis demonstrated that markers of T cell dysfunction associated with HIV were linked to a reduced antibody boost and a faster decline in antibody levels. PLWH with lower counts of functionally-competent CD4 T cells or naïve CD8 T cells showed a diminished humoral response, highlighting the challenges in achieving long-lasting immunity in this population.

Cellular immunity

• T cell polyfunctionality: Although the overall frequency of SARS-CoV-2–specific T cells remained relatively stable, we observed a transient boost in the polyfunctionality of both CD4 and CD8 T cells at T1. Polyfunctional T cells, which produce multiple cytokines simultaneously, are considered critical for protection against severe disease.
• Cross-reactivity: Overall, the T cell responses were similarly reactive against both the ancestral virus and the BA.4/5 variants, suggesting that T cell-mediated protection may be less influenced by immunologic imprinting compared to antibody responses.

Implications for vaccination strategies and future research

Our findings have several important implications:

• For vaccine strategy: The bivalent booster’s ability to enhance BA.4/5–specific responses supports its use in vulnerable populations, including PLWH. However, the rapid decline in antibody levels suggests that additional booster doses or alternative vaccination strategies may be needed to maintain prolonged protection.
• For people living with HIV: PLWH on effective ART were able to mount a comparable immune response to HIV-negative individuals. This is encouraging for vaccination strategies targeting immunocompromised populations.
• For future research: Immunologic imprinting remains a crucial area for further study. Understanding how to “retrain” the immune system to respond more flexibly to new variants could improve vaccine design, not only for COVID-19 but also for other rapidly evolving pathogens.

Concluding thoughts

Our study has highlighted the potential of using a variant-adapted booster to enhance immune protection in PLWH. While the booster induced a robust yet transient antibody response and maintained stable cellular immunity, the challenges posed by immunologic imprinting and HIV-associated T cell dysfunction indicate that further research is needed.

As we continue to explore the intricacies of immune memory and vaccine responsiveness, our findings contribute to refining vaccination strategies for the most vulnerable populations.