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Using data from the CoVPN 3008 study, the authors show that the neutralizing antibody correlate of risk holds in people living with HIV. However, the nAb correlate was weaker and shorter-lived in a vaccine-immunity versus hybrid-immunity population.

The extraordinary diversity of HIV is a major barrier in the path of developing a vaccine. One way forward may be mosaic antigens—biometrically designed genes that maximize overlap between sequences used in the vaccine and circulating HIV-1 strains worldwide (pages 319–323 and 324–328).

BCG revaccination of adolescents has been shown to provide some protection against sustained infection with Mycobacterium tuberculosis. Here, using intracellular cytokine staining and CITE-Seq, the authors identify several effector memory CD4⁺ T cell populations in adolescents revaccinated with BCG that can aid the search for correlates of protection.

Small molecule drugs can affect clearance of monoclonal antibodies, but this hasn’t been assessed for oral HIV-1 pre-exposure prophylaxis. Here, the authors find that faster serum clearance of an experimental IgG1 monoclonal antibody, VRC01, is associated with use of tenofovir-emtricitabine, possibly explained by increased epithelial intestinal permeability.

The US National Institute of Allergy and Infectious Diseases (NIAID) convened a virtual workshop in July 2022 to address the research landscape and identify gaps and opportunities in the understanding of durable vaccine protection.

Antibody immunoprophylaxis for HIV-1 will require effective concentration of biologics at mucosal sites of exposure for effectivity. Here the authors show that infused Fc-modified VRC01LS antibody has increased levels in blood, in the female genital tract and male rectal tissue, compared to native antibody VRC01. VRC01LS is detectable for more than year at the sites of sexual HIV transmission.

Analytical gaps limit the utility of scATAC-seq for studying gene regulatory programs in human disease. Here, authors describe MOCHA, a robust analytical tool with advanced statistical modelling that enables functional genomic inference in large cross-sectional and longitudinal human studies.

Morgane Rolland and colleagues report that in HIV infection, a higher diversity of infecting founder viruses is associated with markers of poorer clinical outcome.

The expression of antibodies to protect against an infectious disease can be achieved by the injection into the host of vectors carrying the gene to the relevant antibodies. Here the authors demonstrate the applicability of this technique to protection from HIV in a humanized mouse model, showing this to be a valid route to pursue in vaccine development for humans (pages 296–300).

Infection by HIV requires the virus to breach the mucosal barrier to gain access to the immune cells that it infects. But what are the immediate events that follow HIV exposure at genital mucosal sites and what are the key cells that facilitate HIV invasion?

T cell bystander activation is induced by systemic inflammation. Here the authors show, using mouse model systems and correlating with human vaccination data, that localized inflammation elicits bystander activation, and that CXCR3 specifically recruits memory CD8⁺ T cells to sites of activated antigen-presenting cells for bystander activation.

Long COVID or post-acute sequelae of SARS-CoV-2 is defined by persisting chronic symptoms following acute SARS-CoV-2 infection but represent an aetiologically diverse group of disorders. Here authors identify molecularly distinct subtypes, including a form with persistent inflammation, via longitudinal analysis of serum proteome.

The RV144 vaccine trial showed reduced risk of HIV-1 acquisition, but mechanisms underlying protection are poorly understood. Here, Fourati et al. assess the transcriptomic profile of blood collected from 223 vaccinees and 40 placebo recipients and identify IRF7 as a mediator of protection.

In vivo deuterium labelling reveals a quiescent population of long-lived human virus-specific memory CD8 T cells that maintain the epigenetic landscape of effector cells, which facilitates rapid responses to pathogen re-exposure.

The STEP HIV-1 vaccine trial failed to protect volunteers from infection, but whether vaccine-driven immune responses affected the profile of viral variants in infected individuals was unknown. By analyzing nucleotide sequences and predicted T cell epitopes in viruses from newly infected trial participants, Rolland et al. now report that the degree of viral divergence from vaccine-encoded inserts suggests that vaccine-induced T cell responses indeed influenced the viral repertoire, a finding that might be harnessed in future vaccine design.

Specific variants of the human leukocyte antigens HLA-B27 and HLA-B57 are associated with control of HIV-1 infection, but the mechanisms responsible for this protection are not clear. Here, Elahi et al. show that CD8⁺ cytotoxic T cells restricted by these HLA variants are less susceptible to suppression by and are able to kill regulatory T cells, which may account for their sustained proliferative capacity during chronic HIV-1 infection.

Mielke et al. perform a multi-assay analysis of humoral and adaptive cellular responses to SARS-CoV-2 in people with HIV compared to people without HIV. Using supervised machine learning tools and network analysis, the authors find differences in the immune profile and anti-endemic coronavirus immune response between these two populations.

Donor-derived, EBV-specific CD8⁺ T cells engineered to express a high-affinity WT1-specific TCR established persistent T cell responses that safely prevented post-HCT relapse in patients with high-risk AML.

Computational analysis of antigen-specific T cell subsets highlights individual-level variation in immune response quality.

The US National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institute of Health (NIH), convened a virtual workshop on August 8-9^th, 2023 to explore potential synergies between HIV vaccine approaches that are designed to induce cellular or humoral immune responses. The goal of this workshop was to review data on leading vaccine candidates and to discuss the best strategies for combining these approaches to optimize immunity against HIV. Here, we summarize the findings reviewed at the workshop and discuss the knowledge gaps and priorities for future studies that will help accelerate the development of a preventive HIV vaccine.

Calder, Tong et al. discuss how the rapid development of COVID-19 vaccines benefited from HIV/AIDS research. They highlight lessons learned from the COVID-19 vaccine development experience that could accelerate and re-energize the development of a safe and efficacious HIV vaccine.