International AIDS Vaccine Initiative

Background/Objectives: The rapid development of safe and efficacious vaccines is often hindered by extensive, mandated non-clinical safety evaluations in animals. With the aim to provide scientific evidence supporting a "vaccine platform approach", here we present the complete non-clinical studies for two investigational vaccines, GRAd-COV2 and GRAdHIVNE1, based on GRAd, a gorilla-derived group C adenoviral vector. Methods: The biodistribution of GRAd genomes following the intramuscular administration of the vaccines was assessed in rats by a sensitive qPCR method. Local tolerance and systemic toxic effects were evaluated in single- and repeated-dose toxicity studies in rabbits. Results: GRAd-COV2 and GRAdHIVNE1 were well-tolerated. Distribution was highly confined to the injection site and draining lymph nodes, and toxicity profile consisted of transient, non-adverse inflammatory responses, while the expected immune responses to the encoded antigens were successfully induced. Notably, both vaccines demonstrated a consistent safety profile despite transgene and backbone differences, comparable to other replication-defective adenoviral vectors. Conclusions: The established non-clinical safety profile of the GRAd platform provides a robust foundation for a more efficient and streamlined regulatory pathway. By leveraging this prior knowledge, future GRAd-based vaccines can achieve accelerated clinical development while fully adhering to the ethical principles of replacement, reduction, and refinement of animal use in research.

Brucellosis is a widespread zoonotic disease and a major contributor to febrile illness, often underdiagnosed. This study investigated the seroprevalence of brucellosis and the associated exposure factors within South African farming and animal health communities. A cross-sectional survey was conducted across 40,000 km2 in the Free State and Northern Cape provinces from 2015 to 2016. Interviews and serum samples were collected from 847 volunteers on randomly selected farms and veterinary professionals listed in a regional register. Samples were tested using a commercial Brucella IgG ELISA. Risk factors were assessed using logistic regression, accounting for within-farm clustering. The seroprevalence was higher among veterinary professionals (11.6%; 16/138) than farm-based participants (7.0%; 50/711); p = 0.095. Multivariable analysis identified several exposure factors within the farm-based population: age over 40 years (aOR = 5.35; 95% CI: 1.68–17.02), White population group (aOR = 4.60; 95% CI: 1.64–12.91), contact with diseased animals (aOR = 2.01; 95% CI: 1.05–3.84), and working 4–8 h daily with ungulates (aOR = 2.90; 95% CI: 1.25–6.76). Among veterinary professionals, odds of exposure were higher with more than 5 years of work (OR = 1.82; 95% CI: 1.21–2.72) and extended ungulate contact (OR = 4.85; 95% CI: 1.27–18.52). Occupational exposure highlights the need for improved brucellosis prevention strategies.

Background/Objectives: Despite progress in antiretroviral therapy, HIV remains a major global health challenge with over one million new infections annually. An effective vaccine is urgently needed. Germline-targeting immunogens show promise in initiating broadly neutralizing antibody (bNAb) precursors. This study developed a scalable, cGMP-compliant process to manufacture the HIV vaccine booster immunogen HxB2.WT.Core-C4b, a nanoparticle designed to direct bNAb precursor maturation after priming. Methods: A CHO cell platform was established through single-cell cloning from a high-producing stable pool. Upstream and downstream processes were optimized for scalability and yield. Three scales were tested 10 L, 40 L, and 400 L. Key parameters (pH, temperature, feeding, metabolite profiles) were systematically refined. Analytical characterization included glycosylation profiling, electron microscopy, and antigenicity testing. Viral clearance was evaluated per ICH Q5A guidelines. Results: Optimization ensured consistent yields above 130 mg/L, with titers up to 250 mg/L. The selected clone (4E22) demonstrated strong growth, viability, and reproducibility. Glycan occupancy at 18 N-linked sites, including bNAb epitopes (N276, N332), was stable across scales. Over 70% of self-assembling nanoparticle were fully assembled at the GMP level. Antigenicity and purity met cGMP release criteria. Viral clearance achieved >13-log reduction for enveloped and >7-log for non-enveloped viruses. Conclusions: This work establishes a robust, scalable platform for HIV nanoparticle immunogens. Consistent quality and yield across scales support clinical development of HxB2.WT.Core-C4b and provide a model for other glycosylated nanoparticle vaccines. The immunogen is being evaluated in clinical study HVTN 320 (NCT06796686), enabling early testing of next-generation vaccines designed to elicit broadly neutralizing antibodies.

HIVR4P 2024, the 5th HIV Research for Prevention Conference, took place in Lima, Peru, 6-10 October 2024. The conference focused on new developments in HIV prevention from basic research to new product development and implementation science. Sessions were assigned to one of five tracks: basic science; pre-exposure prophylaxis (PrEP) and antiretroviral (ARV)-based prevention; vaccines and broadly neutralizing antibodies (bNAbs); applied and implementation science; and other prevention modalities and cross-cutting issues. A team of rapporteurs covered each track and identified conference highlights. Strategies to elicit bNAb responses by vaccination are advancing to clinical trials, while combination bNAbs show promise as an alternative to ARV-based products. There is promising diversity in the PrEP product pipeline and twice-yearly lenacapavir has demonstrated exceptional efficacy, but barriers to widespread access and implementation remain, compounded by new challenges from the significant policy changes and funding reductions of the new US administration. Innovative ways of delivering PrEP to vulnerable communities that could benefit are being explored and, in some cases, have been successfully implemented. Choice in HIV prevention products and differentiated delivery models that enable clients to select options that meet their preferences and changing needs is essential. Additionally, the involvement of the community throughout the design, implementation and dissemination process is necessary to maximize the impact of HIV prevention. Ensuring equitable access in a rapidly changing context will involve policy changes, partnerships with local organizations and addressing social determinants that impact health outcomes. We are in an era with more tools than ever before to prevent HIV acquisition; now, we need to facilitate collaborations between diverse stakeholders, including researchers, community members, policymakers, healthcare providers and funders. The future of HIV prevention should lie in a holistic approach that respects individual choice, enhances service accessibility and is flexible to meet evolving challenges and opportunities. However, policy changes since the conference ended have profoundly altered the HIV prevention landscape and threaten the advances described in this report.

Rice blast remains a major disease, causing severe yield losses in rice-producing regions and posing a threat to global food security. Understanding genetic variation within germplasms is crucial for identifying locally adapted genotypes with beneficial alleles for improving resistance to this disease. In this study, we evaluated the genetic diversity of 261 East and Southern African (ESA) rice accessions and their relationship with the global 3K rice diversity panel. Additionally, marker-trait associations (MTAs) for leaf blast (BL) resistance were analyzed using the settlement of mixed linear model under progressively exclusive relationship (SUPER) and Bayesian information and Linkage-disequilibrium Iteratively Nested Keyway (BLINK) genome-wide association study (GWAS) models. Our findings revealed five sub-populations within the ESA panel, exhibiting considerable genetic diversity. Interestingly, the ESA panel differed from most 3K accessions, forming a distinct diversity cluster within the indica and aus genetic subgroups. Nucleotide diversity (π) ranged from moderate to high (0.10−0.45) among these accessions, with the highest diversity hotspots detected between 29 and 45 Mb. Both GWAS models identified several MTAs linked to BL resistance, with significant MTAs on chromosome 4 explaining 20.6% of genetic variance. Linkage analysis of chromosome 4 uncovered a major quantitative trait locus (QTL), qBL4, spanning positions 30.06−30.23 Mb. This QTL harbors several candidate genes, including LOC_Os04g51030, which encodes a wall-associated protein kinase (WAK). Haplotypes containing favorable alleles of this gene demonstrated an average disease reduction of 1.6 on a 0–9 scale. These haplotypes represent a valuable genetic resource for breeding durable, broad-spectrum rice blast-resistant varieties.

Abstract One challenge in vaccine development is designing immunogens that elicit durable immunity. We hypothesized that antigen avidity regulates the magnitude, diversity, and durability of the vaccine immune response. We tested this in multiple preclinical HIV vaccine models using a neoteric mosaic nanoparticle platform. This allowed us to precisely modulate antigen avidity by varying multivalency and affinity independently, whilst keeping other variables constant. Antigen avidity drove seeding, interclonal competition, and immunodominance within germinal centers. High-valency immunogens promoted durable germinal center, memory B cell, serum antibody, and long-lived plasma cell responses. Restricting interclonal competition rescued B cell responses to low-valency immunogens. B cell receptor sequencing revealed that antigen valency had minimal impact on individual somatic hypermutations but promoted clonal diversity. Affinity worked in concert with valency in driving productive B cell responses, with multivalency having dominant influences. The results underscore the importance of antigen avidity in driving durable and diverse vaccine responses.

IntroductionMaternal mortality remains a critical global health issue, with ongoing efforts to reduce its incidence as part of international health priorities. Kenya, a sub-Saharan country that has a disproportionate number of maternal mortality is likely to miss this target unless evidence-based interventions are deployed. The paucity of reliable maternal health data calls for the development of alternative predictive models to complement the impaired civil registration system and the aperiodic national surveys.MethodsWe utilized DHS surveys from several Sub-Saharan African countries to estimate parameters for predicting Kenya’s maternal mortality rate (MMR) in the absence of recent Kenya Demographic and Health Survey (KDHS) data. We developed a multiple linear regression model using supervised machine learning using the R-programming suite. Our model leverages machine learning techniques to analyze regional trends and predict sub-national MMR variations. We then applied the model to predict MMR for Kenyan counties using the data for the KDHS 2022 survey. ResultsUsing Pearson’s correlation, we observed a significant positive correlation between MMR and total fertility (r = 0.32, p = 0.025) and a significant negative correlation between MMR and maternal age at first birth (r = -0.40, p = 0.005). Additionally, a significant correlation was observed with the cumulative percentage of mothers attending post-natal clinics, the prevalence of thinness (r = 0.77, p < 0.001), HIV infection in women (r = 0.20, p = 0.164), and physical violence during pregnancy. The model estimate of national MMR in 2022 was 367 deaths per 100,000 live births, ranging from 49 deaths per 100,000 live births in Kisii County to 1794 deaths per 100,000 live births in Turkana County.ConclusionAlthough MMR in Kenya displayed a general downward trend, our model’s estimates for DHS 2022 indicate an increase compared to the 2019 National Census and Housing Survey estimate of 355 deaths per 100,000 live births. This rise may be attributed to COVID-19-related maternal deaths during the same period. The integration of predictive models to inform interventions and resource allocation could play a crucial role in enhancing maternal healthcare outcomes in Kenya.

Spontaneous control of chronic-phase HIV/SIV viremia is often associated with the expression of specific MHC class I allotypes. HIV/SIV-specific CD8+ cytotoxic T lymphocytes (CTLs) restricted by these MHC class I allotypes appear to be critical for viremic control. Establishment of the elite controller (EC) phenotype is predictable in SIVmac239-infected Indian rhesus macaques (RMs), with approximately 50% of Mamu-B*08+ RMs and 20% of Mamu-B*17+ RMs becoming ECs. Despite extensive characterization of EC-associated CTLs in HIV/SIV-infected individuals, the precise mechanistic basis of elite control remains unknown. Because EC and non-EC viral load trajectories begin diverging by day 14 post-infection, we hypothesized that hyperacute innate immune responses may contribute to viremic control. To gain insight into the immunological factors involved in the determination of EC status, we vaccinated 16 Mamu-B*08+ RMs with Vif and Nef to elicit EC-associated CTLs, then subjected these 16 vaccinees and an additional 16 unvaccinated Mamu-B*08+ controls to repeated intrarectal SIVmac239 challenges. We then performed whole-blood transcriptomic analysis of all 32 SIVmac239-infected Mamu-B*08+ RMs and eight SIVmac239-infected Mamu-B*08 - RMs during the first 14 days of infection. Vaccination did not provide protection against acquisition, but peak and setpoint viremia were significantly lower in vaccinees relative to controls. We did not identify any meaningful correlations between vaccine-induced CTL parameters and SIVmac239 acquisition rate or chronic-phase viral loads. Ultimately, 13 of 16 vaccinees (81%) and 7 of 16 controls (44%) became ECs (viremia ≤ 10,000 vRNA copies/mL plasma for ≥ 4 weeks). We identified subsets of immunomodulatory genes differentially expressed (DE) between RM groupings based on vaccination status, EC status, and MHC class I genotype. These DE genes function in multiple innate immune processes, including the complement system, cytokine/chemokine signaling, pattern recognition receptors, and interferon-mediated responses. A striking difference in the kinetics of differential gene expression among our RM groups suggests that Mamu-B*08-associated elite control is characterized by a robust, rapid innate immune response that quickly resolves. These findings indicate that, despite the association between MHC class I genotype and elite control, innate immune factors in hyperacute SIV infection preceding CTL response development may facilitate the establishment of the EC phenotype.

The induction of durable protective immune responses is the main goal of prophylactic vaccines, and adjuvants play an important role as drivers of such responses. Despite advances in vaccine strategies, a safe and effective HIV vaccine remains a significant challenge. The use of an appropriate adjuvant is crucial to the success of HIV vaccines. Here we assessed the saponin/MPLA nanoparticle (SMNP) adjuvant with an HIV envelope (Env) trimer, evaluating the safety and impact of multiple variables including adjuvant dose (16-fold dose range), immunization route, and adjuvant composition on the establishment of Env-specific memory T and B cell responses (T Mem and B Mem ) and long-lived plasma cells in non-human primates. Robust B Mem were detected in all groups, but a 6-fold increase was observed in the highest SMNP dose group vs. the lowest dose group. Similarly, stronger vaccine responses were induced in the highest SMNP dose for CD40L + OX40 + CD4 T Mem (11-fold), IFNγ + CD4 T Mem (15-fold), IL21 + CD4 T Mem (9-fold), circulating T FH (3.6-fold), bone marrow plasma cells (7-fold), and binding IgG (1.3-fold). Substantial tier-2 neutralizing antibodies were only observed in the higher SMNP dose groups. These investigations highlight the dose-dependent potency of SMNP in non-human primates, which are relevant for human use and next-generation vaccines.

Germline-targeting (GT) protein immunogens to induce VRC01-class broadly neutralizing antibodies (bnAbs) to the CD4 binding site (CD4bs) of the HIV Envelope have shown promise in clinical trials. Here, we preclinically validated a lipid nanoparticle (LNP)–encapsulated nucleoside mRNA (mRNA-LNP) encoding eOD-GT8 as a soluble self-assembling 60mer nanoparticle in mouse models. In a model with three humanized B cell lineages bearing distinct VRC01-precursor B cell receptors (BCRs) with similar affinities for eOD-GT8, all lineages could be simultaneously primed and undergo diversification and affinity maturation without exclusionary competition. Boosts drove precursor B cell participation in germinal centers, the accumulation of somatic hypermutations, including in key VRC01-class positions, and affinity maturation to boost and native-like antigens in two of the three precursor lineages. We have preclinically validated a prime–boost regimen of soluble self-assembling nanoparticles encoded by mRNA-LNP, demonstrating that multiple lineages can be primed, boosted, and diversified along the bnAb pathway.