Calman Alexander MacLennan

Background: Gonorrhea, a bacterial sexually transmitted infection caused by Neisseria gonorrhoeae, is a major global public health concern due to rising incidence and increasing antimicrobial resistance. Absence of a licensed vaccine and limitations of animal models have impeded progress in the understanding of pathogenesis, immunity, and development of novel therapeutics and vaccines. Controlled human infection studies (CHIS) offer a powerful approach to accelerate vaccine and antimicrobial development and improve understanding of host–pathogen interactions. Methods: An international, multidisciplinary stakeholder workshop was convened in Oxford, United Kingdom (March 2025), to review current gonorrhea CHIS activity, define research priorities, and establish consensus standards for future studies through structured discussion. Results: Consensus highlighted the continued value of CHIS with well-characterized strains such as FA1090, while supporting careful selection and characterization of novel strains. Standardized, risk-based approaches to inoculum manufacture and quality assurance were recommended to enhance reproducibility and scalability. Expansion of CHIS to include additional anatomical sites and novel populations, including individuals with female reproductive anatomy, was identified as scientifically valuable but requiring careful ethical and safety evaluation. CHIS were recognized as uniquely positioned to advance vaccine and antimicrobial development by enabling early efficacy assessment, identification of correlates of protection, and optimization of treatment and prevention strategies. Conclusions: Gonorrhea CHIS are an underutilized but valuable research tool with potential to accelerate translational research against gonorrhea. With robust ethical oversight, community engagement, and international collaboration, expanded and harmonized CHIS could substantially advance prevention and treatment strategies.

Neisseria gonorrhoeae poses significant public health challenges due to multidrug-resistant gonorrhea and severe reproductive health complications of untreated infection. No vaccine is licensed to prevent gonorrhea. However, the meningococcal outer membrane vesicle (OMV)-containing vaccine, 4CMenB, provides moderate cross-protection against gonorrhea. We have recently demonstrated that immunization with gonococcal OMV accelerates clearance of gonococcal infection in mice compared with 4CMenB. To gain insight into possible mechanisms of protection of gonococcal OMV, we evaluated the immunogenicity of GonoVac, a candidate native OMV (nOMV) vaccine against gonorrhea, in mice and rabbits. Three doses of GonoVac were administered intramuscularly from 0.15 to 5 µg in mice, and four doses were used to immunize rabbits at 50 µg per dose, formulated with or without aluminum hydroxide [Al(OH) ₃ ]. Systemic and mucosal antibody responses were evaluated by enzyme-linked immunosorbent assay (ELISA) and serum bactericidal assay (SBA). Cellular responses were assessed by enzyme-linked immunosorbent spot (ELISpot3). Immunization with GonoVac formulated with and without Al(OH) ₃ induced significantly higher levels of gonococcal serum and vaginal IgG, and serum bactericidal antibodies, compared with 4CMenB, which induced no serum killing activity. Serum bactericidal activity of GonoVac correlated with anti-gonococcal IgG2a and IgG3 levels. Serum IgA levels were minimal. Cellular immune responses were higher in mice receiving GonoVac/Al(OH) ₃ compared with GonoVac alone. Immunogenicity was similar for GonoVac produced in a bioreactor and shake flasks. GonoVac elicits robust and functional immune responses in mice and rabbits compared with 4CMenB, supporting its further development as a promising candidate vaccine against gonorrhea. IMPORTANCE: Gonorrhea, caused by Neisseria gonorrhoeae , remains a significant global health concern, disproportionately affecting populations in low- and middle-income countries (LMICs), particularly women. The emergence of multidrug-resistant strains of N. gonorrhoeae has raised the concern of untreatable gonorrhea, underscoring the urgent need for effective preventive measures. Although there is no licensed vaccine against gonorrhea, the meningococcal OMV-based vaccine, 4CMenB, is partially effective against the disease and has been recommended for use in high-risk groups. In this article, we build on previous findings of enhanced efficacy of gonococcal OMV vaccine candidates compared with 4CMenB in the mouse gonococcal infection model to demonstrate the superior anti-gonococcal immunogenicity of a gonococcal OMV-based candidate vaccine (GonoVac) compared with 4CMenB. GonoVac elicits robust immunity in mice, inducing antibodies that are able to kill gonococci, whereas 4CMenB does not. The findings highlight the potential of GonoVac as a promising vaccine candidate for the prevention of gonorrhea worldwide.

Neisseria gonorrhoeae causes 82 million global cases of gonorrhoea annually. Multidrug-resistant gonococci threaten to make gonorrhoea untreatable. Meningococcal vaccines MeNZB and 4CMenB (Bexsero), containing Neisseria meningitidis group B detergent-extracted outer membrane vesicles (dOMV), cross-protect against gonorrhoea with 31–59% effectiveness. We hypothesised that gonococcal OMV-based vaccines would have greater efficacy against gonorrhoea than meningococcal vaccines. We developed native OMV (nOMV) candidate Neisseria vaccines from gonococcal strains GC_0817560 and FA1090, and meningococcal B strain NZ98/254. lpxL1 and rmp genes were deleted to reduce reactogenicity and minimise induction of unprotective or blocking antibodies. nOMV were characterised and formulated with aluminium hydroxide. Deletion of lpxL1 markedly reduced nOMV-induced IL-6 release from peripheral blood mononuclear cells. nOMV derived from GC_0817560 lpxL1 ⁻ rmp ⁻ and FA1090 lpxL1 ⁻ rmp ⁻ induced greater quantities of gonococcal-specific serum IgG and accelerated clearance of FA1090 from oestradiol-treated BALB/c mice significantly faster than 4CMenB and NZ98/254 lpxL1 ⁻ rmp ⁻ nOMV ( P < 0.0001). Gonococcal nOMV-based vaccines represent promising candidates for further development.

Seroprevalence studies can indicate the age-distribution of first infection with non-typhoidal Salmonella (NTS) and estimate the rate of infection by age. We collected 1254 paired samples of serum and stool from healthy children and adults in Kilifi, Nairobi, and Siaya counties in Kenya, areas of low, medium and high incidence of invasive NTS disease (iNTS), respectively. We quantified the age and site-specific geometric mean concentrations (GMCs) of IgG and IgA antibodies against S. Enteritidis O-antigen (O:9, serogroup D) and S. Typhimurium O-antigen (O:4,5, serogroup B) using an in-house standardised ELISA. Serum concentrations were estimated against a previously calibrated reference serum. Maternally derived O:9 IgG and O:4,5 IgG antibodies were detectable in 100% of neonates and the GMC decreased by 40% (95%CI [25%-52%]) per month in the first six months of life. GMCs of IgA were low in neonates. After age 6 months, the O:9 and O:4,5 IgG and IgA GMCs increased sharply with age across all sites, reaching a plateau in early adulthood. The rate of increase in IgG GMCs by age was highest for O:9 in Nairobi, and for O:4,5 in Kilifi. Mixture modelling defined a threshold of 14.1 AU for O:9 IgG and 28.2 AU for O:4,5 IgG. Seroprevalence also increased by age. The GMCs of O:4,5 IgG were 2 times higher for carriers of serogroup B Salmonella than non-carriers. Maternal antibodies to non-typhoidal Salmonella decay rapidly from 0-5months after which incident infection with both serogroups occurs. To be effective, control efforts should be implemented before primary infection.

Vaccines for humans and animals represent an attractive means to counter the growing global pandemic of antimicrobial resistance (AMR). However, vaccines are only available against a few key bacterial pathogens, and interactions between the human and veterinary vaccine communities have been limited. In April 2024, a Royal Society Science+ Meeting on ‘Vaccines and AMR: from science to policy’ was held in London to review the science of how vaccines reduce AMR, identify research gaps in developing AMR vaccines and discuss policy in advancing development and equitable deployment of such vaccines. Taking a One Health approach, the meeting brought together clinical and veterinary experts from academia and industry, policymakers and funders, from high-income countries and from low- and middle-income countries. Articles based on presentations at the Science+ meeting, including an overall summary of the meeting, its outcomes and recommendations, are included in this issue of Philosophical Transactions of the Royal Society B. This opening article provides the background, rationale and aims of the meeting. This article is part of the Royal Society Science+ meeting issue ‘Vaccines and antimicrobial resistance: from science to policy’.

The COVID-19 pandemic demonstrated the capacity of the world to rapidly mobilize resources and political will when faced with an immediate, visible global threat. The accelerated development of effective vaccines inspired the Coalition for Epidemic Preparedness Innovations to promote the 100 Days Mission (100DM), an initiative to enable deployment of medical countermeasures within 100 days of identifying a pandemic threat. The success of the 100DM in uniting stakeholders highlights the power of framing challenges to inspire collective action. On the other hand, antimicrobial resistance (AMR) has had insufficient visibility and urgency to galvanize similar levels of political action. Framing AMR in a way that highlights the urgency, aligns incentives and builds multisectoral coalitions can help overcome some of these barriers. Ultimately, pandemic preparedness and AMR are both collective action problems, requiring sustained political will and systemic change. The AMR community must build systems that are agile and resilient and, by creating a unifying vision for AMR analogous to the 100DM, may promote global commitment to combating this slow-moving but devastating health crisis. This article is part of the Royal Society Science+ meeting issue ‘Vaccines and antimicrobial resistance: from science to policy’.

In April 2024, the Royal Society convened a Science+ meeting in London on ‘Vaccines and antimicrobial resistance: from science to policy’. The purpose was to review the science of how vaccines reduce antimicrobial resistance (AMR) and discuss policy in advancing development and equitable deployment of such vaccines. The meeting adopted a One Health approach with international speakers presenting from both human and veterinary perspectives. Presentations on Day 1 focused on scientific aspects of the AMR threat and the role of vaccines as counter measures. On Day 2, presentations covered associated policy implications based on this scientific understanding. A closing panel discussion looked towards the United Nations High-Level Meeting on AMR in New York in September 2024. This article is the closing contribution to an issue of Philosophical Transactions of the Royal Society B based on the meeting. It serves as a summary of the two days of proceedings, including key outcomes and recommendations, and provides an overall conclusion to the meeting. This article is part of the Royal Society Science+ meeting issue ‘Vaccines and antimicrobial resistance: from science to policy’.

Background: Shigellosis is the leading cause of diarrheal deaths worldwide and is particularly dangerous in children under 5 years of age in low- and middle-income countries. Additionally, the rise in antibiotic resistance has highlighted the need for an effective Shigella vaccine. Previously, we have used the Multiple Antigen-Presenting System (MAPS) technology to generate monovalent and quadrivalent Salmonella MAPS vaccines that induce functional antibodies against Salmonella components. Methods: In this work, we detail the development of several monovalent vaccines using O-specific polysaccharides (OSPs) from four dominant serotypes, S. flexneri 2a, 3a, and 6, and S. sonnei. We tested several rhizavidin (rhavi) fusion proteins and selected a Shigella-specific protein IpaB. Quadrivalent MAPS were made with Rhavi-IpaB protein and tested in rabbits for immunogenicity. Results: Individual MAPS vaccines generated robust, functional antibody responses against both IpaB and the individual OSP component. Antibodies to IpaB were effective across Shigella serotypes. We also demonstrate that the OSP antibodies generated are specific to each homologous Shigella O type by performing ELISA and bactericidal assays. We combined the components of each MAPS vaccine to formulate a quadrivalent MAPS vaccine which elicited similar antibody and bactericidal responses compared to their monovalent counterparts. Finally, we show that the quadrivalent MAPS immune sera are functional against several clinical isolates of the serotypes used in the vaccine. Conclusions: This quadrivalent MAPS Shigella vaccine is immunogenicity and warrants further study.