Developing durable cellular immunity remains a critical challenge for HIV vaccine development.
We evaluated a sequential and repeated heterologous prime-boost vaccination regimen using four distinct vector-based vaccines (DNA, rAd5, rSeV, and rMVA) expressing HIV-1 gag in rhesus macaques over a decade-long observation period.
Compared to the two-vector and control groups, the four-vector regimen elicited potent gag-specific cellular immune responses, as evidenced by IFN-γ ELISPOT assays showing sustained responses exceeding 500 SFCs/106 PBMCs for up to 52 or 69 weeks post-vaccination. Intracellular cytokine staining revealed multifunctional CD4+ and CD8+ T-cell responses, while humoral immunity against Ad5 vectors remained manageable despite repeated administrations.
These findings demonstrate that sequential and repeated heterologous vaccination effectively induces and maintains durable cellular immunity, providing a strategic framework for HIV vaccine design.

Newly approved subunit and mRNA vaccines for respiratory syncytial virus (RSV) demonstrate effectiveness in preventing severe disease, with protection exceeding 80% primarily through the generation of antibodies. An alternative vaccine platform called self-amplifying RNA (saRNA) holds promise in eliciting humoral and cellular immune responses. We evaluate the immunogenicity of a lipid nanoparticle (LNP)-formulated saRNA vaccine called SMARRT.RSV.preF, encoding a stabilized form of the RSV fusion protein, in female mice and in non-human primates (NHPs) that are either RSV-naïve or previously infected. Intramuscular vaccination with SMARRT.RSV.preF vaccine induces RSV neutralizing antibodies and cellular responses in naïve mice and NHPs. Importantly, a single dose of the vaccine in RSV pre-exposed NHPs elicits a dose-dependent anamnestic humoral immune response comparable to a subunit RSV preF vaccine. Notably, SMARRT.RSV.preF immunization significantly increases polyfunctional RSV.F specific memory CD4+ and CD8+ T-cells compared to RSV.preF protein vaccine. Twenty-four hours post immunization with SMARRT.RSV.preF, there is a dose-dependent increase in the systemic levels of inflammatory and chemotactic cytokines associated with the type I interferon response in NHPs, which is not observed with the protein vaccine. We identify a cluster of analytes including IL-15, TNFα, CCL4, and CXCL10, whose levels are significantly correlated with each other after SMARRT.RSV.preF immunization. These findings suggest saRNA vaccines have the potential to be developed as a prophylactic RSV vaccine based on innate, cellular, and humoral immune profiles they elicit.
© 2024. The Author(s).

Durable response to chimeric antigen receptor T (CART) cell therapy remains limited in part due to CART cell exhaustion. Here, we investigate the regulation of CART cell exhaustion with three independent approaches including: a genome-wide CRISPR knockout screen using an in vitro model for exhaustion, RNA and ATAC sequencing on baseline and exhausted CART cells, and RNA and ATAC sequencing on pre-infusion CART cell products from responders and non-responders in the ZUMA-1 clinical trial. Each of these approaches identify interleukin (IL)-4 as a regulator of CART cell dysfunction. Further, IL-4-treated CD8+ CART cells develop signs of exhaustion independently of the presence of CD4+ CART cells. Conversely, IL-4 pathway editing or the combination of CART cells with an IL-4 monoclonal antibody improves antitumor efficacy and reduces signs of CART cell exhaustion in mantle cell lymphoma xenograft mouse models. Therefore, we identify both a role for IL-4 in inducing CART exhaustion and translatable approaches to improve CART cell therapy.
© 2024. The Author(s).

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron breakthrough infection (BTI) induced better protection than triple vaccination. To address the underlying immunological mechanisms, we studied antibody and T cell response dynamics during vaccination and after BTI. Each vaccination significantly increased peak neutralization titers with simultaneous increases in circulating spike-specific T cell frequencies. Neutralization titers significantly associated with a reduced hazard rate for SARS-CoV-2 infection. Yet, 97% of triple vaccinees became SARS-CoV-2 infected. BTI further boosted neutralization magnitude and breadth, broadened virus-specific T cell responses to non-vaccine-encoded antigens, and protected with an efficiency of 88% from further infections by December 2022. This effect was then assessed by utilizing mathematical modeling, which accounted for time-dependent infection risk, the antibody, and T cell concentration at any time point after BTI. Our findings suggest that cross-variant protective hybrid immunity induced by vaccination and BTI was an important contributor to the reduced virus transmission observed in Bavaria in late 2022 and thereafter.
© 2024 The Authors.

In this phase III, open label, single arm, multicenter clinical study, we report safety, tolerability and immunogenicity of PHH-1V as a booster dose in subjects primary vaccinated against COVID-19 with the BNT162b2, mRNA-1273, ChAdOx1-S, or Ad26.COV2.S vaccines, with or without previous COVID-19 infection. A total of 2661 subjects were included in this study and vaccinated with the PHH-1V vaccine. Most treatment-emergent adverse events (TEAE) were solicited local and systemic reactions with grade 1 (58.70%) or grade 2 (27.58%) intensity, being the most frequently reported injection site pain (82.83%), fatigue (31.72%) and headache (31.23%). Additionally, immunogenicity was assessed at Baseline and Days 14, 91, 182 and 365 in a subset of 235 subjects primary vaccinated. On Day 14, geometric mean triter (GMT) in neutralizing antibody against SARS-CoV-2 Wuhan and Beta, Delta and Omicron BA.1 variants increased in all primary vaccination with a geometric mean fold raise (GMFR) of 6.90 (95% CI 4.96-9.58), 12.27 (95% CI 8.52-17.67), 7.24 (95% CI 5.06-10.37) and 17.51 (95% CI 12.28-24.97), respectively. Despite GMT decay after day 14, it remains in all cases significatively higher from baseline up to 1 year after PHH-1V booster administration and GMFR against Beta and Omicron BA.1 variants over 3 at 1 year after booster compared to baseline. PHH-1V booster vaccination elicited also a significant RBD/Spike-specific IFN-γ + T-cell responses on Day 14. Overall, PHH-1V vaccine was immunogenic and well-tolerated regardless of the previous primary vaccination scheme received with no reported cases of severe COVID-19 infection throughout the entire study.