While a growing number of invasive non-typhoidal Salmonella (iNTS) vaccine candidates, including trivalent formulations with typhoid conjugate vaccine (TCV), are in early development, the market demand and commercial potential remain unclear. This study presents a novel demand and financial forecast model for a hypothetical trivalent iNTS-typhoid vaccine, designed for introduction in sub-Saharan Africa (sSA). The model includes projected vaccine demand, revenue and profit forecasts, and net present value (NPV) analysis of return on investments required for development, licensure and manufacturing of the trivalent vaccine. By year 12 after forecasted introduction, annual demand for the trivalent vaccine is projected to reach 47 million doses for a 1-dose regimen and 96 million doses for a 2-dose regimen (Scenario 2), generating annual revenues of $94 million USD and $191 million USD, respectively. Despite these projections, the risk-adjusted NPV is negative, suggesting that the market is not commercially viable for industry investment without global health funding to de-risk the investment. This model assumes a significant demand for a trivalent vaccine in sSA and highlights the need for innovative financing to ensure commercial viability of investment in the vaccine’s development and manufacturing, toward addressing a significant public health issue.

Invasive non-typhoidal Salmonella disease represents a major public health challenge, particularly in sub-Saharan Africa, where it is a leading cause of community-acquired bloodstream infections. Despite its significant morbidity and mortality, no licensed vaccines exist. Recognizing this unmet need, multiple global health initiatives and targeted investments have advanced iNTS vaccine development. These efforts have advanced several promising candidates employing diverse platform technologies, including the first iNTS vaccine candidate to enter clinical trials in more than 15 years in 2019. To date, three additional candidates have entered clinical development-two progressing through Phase 2 trials and one currently in a Phase 1/2 study-while many more remain in preclinical development. Several candidates also incorporate antigens targeting Salmonella Typhi or Salmonella Paratyphi A alongside iNTS components to broaden coverage and expand market potential. Despite this progress, scientific, regulatory and commercial challenges persist. In response, global health organizations have intensified efforts to support vaccine development, clarify regulatory pathways and foster engagement with key decision-makers, including through the development of Preferred Product Characteristics and a Full Value of Vaccines Assessment. These coordinated efforts mark a significant step toward enabling and accelerating iNTS vaccine development, ultimately aiming to prevent iNTS disease and its associated health burden.

This study, grounded in the key stakeholders’ perspectives, highlights the critical and immediate need for the development of a new iNTS vaccine. An online survey was conducted among government officials and healthcare providers across eight African countries: Burkina Faso, the Democratic Republic of Congo, Ethiopia, Ghana, Kenya, Malawi, Mozambique, and Nigeria. The framework was built on Spring Boot and Java 8, enabling access via personal computers or mobile phones. A total of 74 out of 84 participants completed the survey. Over 50% indicated that iNTS is both a prevalent and serious disease in their respective countries. The majority (n = 70, 94.6%) identified antibiotics as the most effective treatment for iNTS disease, while 55 (67.6%) participants chose vaccination as the preferred preventive option. Respondents ranked the iNTS vaccine third. Notably, 75.7% (n = 56) emphasized the urgent need for an iNTS vaccine. Barriers to vaccine introduction were identified as insufficient funding (n = 61, 81.4%), limited awareness (n = 49, 79.7%), and challenges related to community acceptance (n = 49, 79.7%). The stakeholders’ perspectives highlight an urgent need for iNTS vaccine development. Accelerated and focused efforts are essential to address the reported pressing challenges and to pursue innovative and promising pathways for advancing iNTS vaccine development.

Vaccinations remain a cornerstone of public health, effectively reducing the burden of infectious diseases, particularly in children. However, the increasing number of routine vaccine injections, especially in low- and middle-income countries (LMICs), has raised concerns among parents and healthcare providers, potentially impacting vaccine acceptance and adherence. This scoping review aims to investigate the number of injections administered across different age groups in LMICs, with a focus on Africa, South and South-East Asia. Data was sourced primarily from the World Health Organization immunization portal, alongside information on vaccines in development from various global health organizations. The study analyzed routine injectable vaccines by age group, examining national immunization schedules to estimate the number of injections and healthcare visits required and the distribution of injections and visits across different regions. The review highlights the complexity of vaccination practices in LMICs, where children receive numerous injections due to the inclusion of multiple vaccines in the Expanded Program on Immunization. The findings suggest that while vaccines are critical for preventing infectious disease, the high number of injections and visits may contribute to vaccine hesitancy, necessitating a reassessment of immunization strategies. For instance, as new vaccines are progressively introduced, the total number of injections administered to infants in particular could rise from the current 12 to between 18 and 26 injections. This review contributes to the ongoing discourse on optimising vaccine delivery, advocating for the adoption of needle-free technologies and combination vaccines to reduce the number of injections and visits to improve vaccine uptake.

Invasive disease caused by non-typhoidal Salmonella serovars (iNTS) occurs with increased risk in the presence of other comorbidities such as malaria, HIV, malnutrition, anaemia and sickle cell disease. While infection with non-typhoidal (NTS) serovars often results in self-limited enterocolitis in high-income settings, in sub-Saharan Africa (SSA) where these risk-comorbidities are common, an invasive (iNTS) disease phenotype is seen, associated with up to 20 % case-fatality ratio, and antimicrobial resistance is both significant and growing. The need to evaluate the potential public health value of vaccines against iNTS disease is increasingly being recognized, and several candidate vaccines are in early development. A better understanding of the global burden and epidemiology of iNTS disease, as well as the potential public health and socio-economic benefits that iNTS vaccines may offer is fundamental to support and justify the investments in vaccine development. In addition, the pathways for licensure, policy recommendations and eventual vaccine prioritization and use in low- and middle-income countries (LMICs) need to be defined. Here, we report on the proceedings of an expert consultation held on 29 November - 1 December 2021 as part of an overall project to develop a Full Value of Vaccines Assessment (FVVA) for iNTS vaccines and in addition to more recent iNTS vaccine developments. Experts at the consultation reviewed the current evidence on iNTS disease and discussed knowledge gaps to be addressed to accelerate vaccine development, licensure and introduction, as well as LMIC perspectives on potential iNTS vaccine use and demand. The learnings from this consultation are critical inputs to inform remaining work under the iNTS FVVA project.

Invasive non-typhoidal serovars of Salmonella enterica,S. Typhimurium and S. Enteritidis, (iNTS) are estimated to cause over 500,000 cases of disease leading to more than 79,000 deaths with a high case fatality ratio of 14.5 %. Most infections occur in infants and young children in LMICs in sub-Saharan Africa where host risk factors for iNTS disease such as malaria, malnutrition, HIV infection, and anemia are common. iNTS disease is observed from birth, with a peak incidence early in the second year of life, declining before the age of 3 years. The prevalence of multiple drug resistance of iNTS has increased markedly by decade, emphasizing the need for effective vaccines. A clinical development plan and regulatory pathway for licensure of iNTS vaccines has been shaped following the development of Preferred Product Characteristics and R&D Roadmap through a series of expert consultations. Several iNTS alone or combined with Typhoid Conjugate Vaccine platforms are in early clinical development. Encouraging safety and immunogenicity data have prompted developers and manufacturers to plan efficacy trials, aligned with regulatory expectations. It is critical to clearly communicate iNTS disease burden in endemic countries and to discuss complexities related to iNTS single component or combination vaccine clinical development with regulators. An essential component is the disease burden in infants less than 6 months of age, which will inform the optimal age of first vaccination (less than or from 6 months), compatibility across national expanded programme on immunization schedules, and whether a booster dose would be needed. Early regulatory guidance is essential to make informed regulatory decisions and to guide the clinical development plan and licensure pathway. Continued communication with public health stakeholders and end-user representatives will effectively contribute to better awareness and education about iNTS disease and protection afforded by vaccination.

INTRODUCTION:Invasive non-typhoidal Salmonella (iNTS) disease is a global health concern, particularly for sub-Saharan Africa. Despite high case fatality risks, there is no vaccine available against the disease. An obstacle to vaccine development is a lack of data on the economic burden of iNTS disease in many parts of the world. The main aim of the current study is to estimate the economic burden of iNTS disease in 123 countries. METHODS:Several multivariate regression models were parameterised with the data obtained from an existing systematic literature review on the economic burden of iNTS disease and all forms of NTS disease. Various model diagnostics were performed to validate the statistical significance of each model outcome, and the most suitable model was selected to predict costs in countries where no data points were available. RESULTS:A generalised linear model with gamma distribution with log link was chosen based on model diagnostics. While the average economic burden per iNTS disease episode ranged from US$341 in Africa to US$2194 in Europe, the total economic burden of iNTS disease was the highest in Africa due to the high burden of the disease in the region. CONCLUSION:The current study indicates that the economic burden of iNTS disease is substantial. Given the scarcity of field-based iNTS disease economic burden estimates, cost extrapolation through an econometric framework can be helpful for understanding the associated cost implications in a resource-limited setting and for informing the cost-effectiveness of public health interventions including future vaccination strategies.

Typhoid Conjugate Vaccine (TCV) has been shown to elicit robust immune responses among adults and children. However, data on long-term immunogenicity are sparse. The International Vaccine Institute has conducted a Phase I clinical trial in The Philippines to investigate safety and immunogenicity among healthy individual 2-45 years old. In this study we present the results of a long-term immunogenicity study - 5 years after a typhoid conjugate vaccine composed of Vi polysaccharide conjugated to diphtheria toxoid (Vi-DT) and Vi-polysaccharide vaccine was administered. In this observational study, we followed up the participants who were vaccinated by either the Vi-DT vaccine or comparator vaccine, the Vi-polysaccharide vaccine, for five years after the enrollment in the phase I study. We assessed the safety and immunogenicity of the Vi-DT vaccine among healthy Filipino adults and children, aged 2-45 years and compared it descriptively to a Vi polysaccharide vaccine. Participants who had received at least one dose of either vaccine and agreed to provide at least one blood sample were enrolled to the study. Blood samples were collected to assess the longevity of immunity using anti-Vi IgG and serum bactericidal antibody (SBA) at three different time points: 3 years, 4 years, and 5 years after the vaccination. Between 30 October 2019 and 13 January 2022, blood samples were collected from 137 participants who had received at least one dose of Vi-DT or Vi polysaccharide vaccine, 3 years post-vaccination. Anti-Vi IgG seroconversion of Vi-DT vaccinees was higher in all age strata; 98.44 % (95 % confidence interval (CI): 91.67, 99.72) at year 3, 100.00 % (95 % CI: 94.08, 100.00) at year 4 and 98.41 % (95 % CI: 91.54, 99.72) at year 5. Anti-Vi IgG GMT was higher in the Vi-DT group among all age strata as well. Seroconversion by SBA in the Vi-DT group was higher in the 18-45 age group calculating 75.00 % (95 % CI: 50.50, 89.82), 86.67 % (95 % CI: 62.12, 96.26), and 60.00 % (95 % CI: 35.75, 80.18) at 3rd, 4th and 5th year post-vaccination, respectively. The Vi-DT vaccine provides immunity for at least five years after vaccination. However, data beyond 5 years would be valuable to inform the need for booster doses.

Observational studies on COVID-19 vaccine effectiveness (VE) have provided critical real-world data, informing public health policy globally. These studies, primarily using pre-existing data sources, have been indispensable in assessing VE across diverse populations and developing sustainable vaccination strategies. Cohort design is frequently employed in VE research. The rapid implementation of vaccination campaigns during the COVID-19 pandemic introduced differential vaccination influenced by sociodemographic disparities, public policies, perceived risks, health-promoting behaviors, and health status, potentially resulting in biases such as healthy user bias, healthy vaccinee effect, frailty bias, differential depletion of susceptibility bias, and confounding by indication. The overwhelming burden on healthcare systems has escalated the risk of data inaccuracies, leading to outcome misclassifications. Additionally, the extensive array of diagnostic tests used during the pandemic has also contributed to misclassification biases. The urgency to publish quickly may have further influenced these biases or led to their oversight, affecting the validity of the findings. These biases in studies vary considerably depending on the setting, data sources, and analytical methods and are likely more pronounced in low- and middle-income country (LMIC) settings due to inadequate data infrastructure. Addressing and mitigating these biases is essential for accurate VE estimates, guiding public health strategies, and sustaining public trust in vaccination programs. Transparent communication about these biases and rigorous improvement in the design of future observational studies are essential.

Getting leptospirosis onto the lists of neglected tropical diseases Leptospirosis is a globally important infectious disease, but neglected to the extent that it’s not on WHO’s or FDA’s neglected tropical diseases lists; this needs to change. Leptospirosis, caused by spirochetes of the bacterial genus Leptospira, poses a significant yet poorly recognized global public health threat. Incomprehensibly, this disease remains neglected by the global health agenda. Leptospirosis is estimated to cause more than a million cases and over 60,000 deaths annually, with case fatality rates of up to 20%. (1) Hence, leptospirosis is the most important zoonotic bacterial disease worldwide. It is common in tropical regions of low- and middle-income countries such as Brazil, India, China, Indonesia, Peru, Sri Lanka, and Thailand, and it affects high-income countries, too, including the United States and Europe.

Clinical trials are the most rigorous scientific and regulated method to investigate the safety and efficacy of vaccines or drugs in pre-licensure stage. Clinical trial design and implementation are complex, time-consuming and involves close engagement with country’s regulatory authority, clinical trial sites, investigators, and the healthcare system. Over the past few decades, a significant number of clinical trials have been conducted in low- and middle-income countries (LMICs), particularly in resource-limited settings. Conducting clinical research in LMICs leads to significant capacity building in terms of training and infrastructure, which adds to the improvement in overall public health benefits of the country. Here, we describe the advances in local capacities, infrastructure and healthcare system following the implementation of clinical trials with the contribution of the International Vaccine Institute at different trial sites in Nepal from 2017 to 2024 in urban, semi-urban, and rural settings. We highlight how, in addition to achieving the study-specific objectives, this experience has built local scientific, ethical, and regulatory oversight capabilities and physical infrastructure. Such positive experiences will provide additional rationale for health research organizations, pharmaceutical companies, and funders to engage in the implementation of further vaccine clinical research with LMICs which bear a heavy burden of infectious diseases.

Background: Inactivated whole-virus vaccination elicits immune responses to both SARS-CoV-2 nucleocapsid (N) and spike (S) proteins, like natural infections. A heterologous Ad26.COV2.S booster given at two different intervals after primary BBIBP-CorV primary vaccination was safe and immunogenic at days 28 and 84. We describe booster-specific and hybrid immune responses followed over 1 year.Methods: This open-label phase 1/2 study was conducted in healthy Thai adults aged ≥18 years who had completed primary BBIBP-CorV primary vaccination between 90-240 (Arm A1; n=361) or 45-75 days (Arm A2; n=104) before enrolment. All received an Ad26.COV2.S booster. We measured anti-S and anti-N IgG antibodies by Elecsys®, neutralizing antibodies by SARS-CoV-2 pseudovirus neutralization assay, and T-cell responses by quantitative interferon (IFN)-γ release assay. Immune responses were evaluated in the baseline-seronegative population (pre-booster anti-N <1.4 U/mL; n=241) that included the booster-effect only subgroup (anti-N <1.4 U/mL at each visit) and the hybrid-immunity subgroup (had SARS-CoV-2 infection, non-study COVID-19 booster and/or anti-N ≥1.4 U/mL). Results: In the booster-effect subgroup, day 336 anti-S GMCs were 131- and 45-fold higher than baseline in Arms A1 and A2, respectively. Neutralizing responses against ancestral SARS-CoV-2 and omicron BA.2 in Arm A1 were 5- and 2-fold higher than baseline at day 168 (2-fold and no increase, respectively, at day 336); IFN-γ remained 5-fold higher than baseline at day 336. In the hybrid immunity subgroup, day 336 anti-S GMCs in A1 were 512-fold higher than baseline; neutralizing responses against ancestral SARS-CoV-2 and omicron BA.2 were 34- and 15-fold higher, respectively, and IFN-γ was 12-fold higher in 18–59-year-olds. Immune responses were lower in Arm A2 and in ≥60-year-olds.Conclusion: A heterologous Ad26.COV2.S booster after primary BBIBP-CorV vaccination induced immune responses that were substantially stronger after the longer pre-boost interval and in those with hybrid immunity, up to 1 year.

Non-typhoidal Salmonella (NTS) infection and invasive non-typhoidal Salmonella (iNTS) infection cause a significant global health and economic burden. This systematic review aims to investigate the reported economic burden of NTS and iNTS infection, identify research gaps, and suggest future research directions. Data from PubMed and Embase databases up to April 2022 were reviewed, and articles were screened based on predefined criteria. Cost data were extracted, categorized into direct medical costs (DMCs), direct non-medical costs (DNMCs), and indirect costs (ICs), and converted into US dollars (year 2022). Data primarily originated from high-income countries (37 out of 38), with limited representation from Africa and resource-limited settings. For inpatients, DMCs were the primary cost driver for both NTS and iNTS illnesses, with estimates ranging from USD 545.9 (Taiwan, a region of China) to USD 21,179.8 (Türkiye) for NTS and from USD 1973.1 (Taiwan, a region of China) to USD 32,507.5 (United States of America) for iNTS per case. DNMCs and ICs varied widely across studies. Although study quality improved over time, methodological differences persisted. This review underscores the lack of economic data on NTS and iNTS in resource-limited settings. It also highlights the need for economic burden data in resource-limited settings and a standardized approach to generate global datasets, which is critical for informing policy decisions, especially regarding future vaccines.

For vaccine development and adoption decisions, the ‘Full Value of Vaccine Assessment’ (FVVA) framework has been proposed by the WHO to expand the range of evidence available to support the prioritization of candidate vaccines for investment and eventual uptake by low- and middle-income countries. Recent applications of the FVVA framework have already shown benefits. Building on the success of these applications, we see important new opportunities to maximize the future utility of FVVAs to country and global stakeholders and provide a proof-of-concept for analyses in other areas of disease control and prevention. These opportunities include the following: (1) FVVA producers should aim to create evidence that explicitly meets the needs of multiple key FVVA consumers, (2) the WHO and other key stakeholders should develop standardized methodologies for FVVAs, as well as guidance for how different stakeholders can explicitly reflect their values within the FVVA framework, and (3) the WHO should convene experts to further develop and prioritize the research agenda for outcomes and benefits relevant to the FVVA and elucidate methodological approaches and opportunities for standardization not only for less well-established benefits, but also for any relevant research gaps. We encourage FVVA stakeholders to engage with these opportunities.

Introduction The COVID-19 pandemic catalyzed unprecedented vaccine innovation, revealing critical shortcomings in achieving equitable vaccine access and underscoring the need for a focused review of the lessons learned to inform future pandemic preparedness, with emphasis on vaccine delivery, equity, and challenges in LMICs.Areas covered We critically analyzed the pandemic vaccine development and distribution journey and the operational mechanisms that facilitated these achievements. For this purpose, we primarily searched pandemic vaccine stakeholder websites, reports, and publications. The analysis extends beyond the scientific narrative to address the ‘how’ of the process while anchoring the discussion on equity and global health security as fundamental to preparing for future pandemics.Expert opinion Drawing on the insights gained from the COVID-19 pandemic, we identify several key challenges requiring immediate attention to fortify preparedness for future pandemics. These are cultivating leadership in the field of vaccinology, guaranteeing equitable global access to diagnostics, therapeutic agents, and vaccines, securing adequate funding for ongoing research and development, ensuring the fair distribution of vaccines, and strategically allocating biomedical manufacturing facilities to ensure a balanced global production capacity. Addressing these challenges is imperative to establish a robust pandemic response framework and mitigate the impact of future global health crises.

The spectrum of diseases caused by Streptococcus pyogenes (Strep A) ranges from superficial to serious life-threatening invasive infections. We conducted a scoping review of published articles between 1980 and 2021 to synthesize evidence of state transitions across the Strep A disease spectrum. We identified 175 articles reporting 262 distinct observations of Strep A disease state transitions. Among the included articles, the transition from an invasive or toxin-mediated disease state to another disease state (i.e., to recurrent ARF, RHD or death) was described 115 times (43.9% of all included transition pairs) while the transition to and from locally invasive category was the lowest ( n = 7; 0.02%). Transitions from well to any other state was most frequently reported (49%) whereas a relatively higher number of studies ( n = 71) reported transition from invasive disease to death. Transitions from any disease state to locally invasive, Strep A pharyngitis to invasive disease, and chronic kidney disease to death were lacking. Transitions related to severe invasive diseases were more frequently reported than superficial ones. Most evidence originated from high-income countries and there is a critical need for new studies in low- and middle-income countries to infer the state transitions across the Strep A disease spectrum in these high-burden settings.

BACKGROUND:Inactivated whole-virus vaccination elicits immune responses to both SARS-CoV-2 nucleocapsid (N) and spike (S) proteins, like natural infections. A heterologous Ad26.COV2.S booster given at two different intervals after primary BBIBP-CorV vaccination was safe and immunogenic at days 28 and 84, with higher immune responses observed after the longer pre-boost interval. We describe booster-specific and hybrid immune responses over 1 year. METHODS:This open-label phase 1/2 study was conducted in healthy Thai adults aged ≥ 18 years who had completed primary BBIBP-CorV primary vaccination between 90-240 (Arm A1; n = 361) or 45-75 days (Arm A2; n = 104) before enrolment. All received an Ad26.COV2.S booster. We measured anti-S and anti-N IgG antibodies by Elecsys®, neutralizing antibodies by SARS-CoV-2 pseudovirus neutralization assay, and T-cell responses by quantitative interferon (IFN)-γ release assay. Immune responses were evaluated in the baseline-seronegative population (pre-booster anti-N < 1.4 U/mL; n = 241) that included the booster-effect subgroup (anti-N < 1.4 U/mL at each visit) and the hybrid-immunity subgroup (anti-N ≥ 1.4 U/mL and/or SARS-CoV-2 infection, irrespective of receiving non-study COVID-19 boosters). RESULTS:In Arm A1 of the booster-effect subgroup, anti-S GMCs were 131-fold higher than baseline at day 336; neutralizing responses against ancestral SARS-CoV-2 were 5-fold higher than baseline at day 168; 4-fold against Omicron BA.2 at day 84. IFN-γ remained approximately 4-fold higher than baseline at days 168 and 336 in 18-59-year-olds. Booster-specific responses trended lower in Arm A2. In the hybrid-immunity subgroup at day 336, anti-S GMCs in A1 were 517-fold higher than baseline; neutralizing responses against ancestral SARS-CoV-2 and Omicron BA.2 were 28- and 31-fold higher, respectively, and IFN-γ was approximately 14-fold higher in 18-59-year-olds at day 336. Durable immune responses trended lower in ≥ 60-year-olds. CONCLUSION:A heterologous Ad26.COV2.S booster after primary BBIBP-CorV vaccination induced booster-specific immune responses detectable up to 1 year that were higher in participants with hybrid immunity. CLINICAL TRIALS REGISTRATION:NCT05109559.

BACKGROUND:With accumulating evidence of single-dose human papillomavirus (HPV) vaccine efficacy in young women, we conducted a community vaccine effectiveness study comparing HPV single-dose and 2-dose regimens (0 and 6 months) of a bivalent HPV vaccine among grade 8 schoolgirls (aged 13-14 years) in Thailand. METHODS:In 2018, eligible grade 8 schoolgirls in Udon Thani (single dose) and Buri Ram (2 doses) provinces were offered HPV vaccine per assigned dose regimen. Concurrently, a cross-sectional survey for measuring baseline HPV prevalence was conducted in grade 10 (n = 2600) and grade 12 unvaccinated schoolgirls (n = 2000) in each province. HPV infection was assessed in first-void urine samples, tested by DNA polymerase chain reaction on the cobas 4800 system (Roche Molecular Diagnostics, Pleasanton, CA). All samples positive on the cobas system and an equal number of negative samples were also tested by Anyplex II HPV28 Detection (Seegene, Seoul, South Korea). The surveys were repeated in 2020 and 2022, when vaccinated grade 8 schoolgirls reached grade 10, and then subsequently grade 12, respectively. Vaccine effectiveness was estimated by comparing the weighted prevalence of HPV-16 or HPV-18 between grade-matched unvaccinated schoolgirls on the baseline survey (2018) and vaccinated schoolgirls in the year-2 (2020) and year-4 (2022) surveys. Adjustment methods were used in the analysis to account for potential differences in sexual behavior due to the noncontemporaneous comparison. RESULTS:The prevalence of HPV-16 and HPV-18 on the baseline survey among unvaccinated grade 10/grade 12 schoolgirls was 2.90% (95% confidence interval [CI] = 2.54% to 3.31%)/3.98% (95% CI = 3.52% to 4.49%) for Udon Thani and 3.87% (95% CI = 3.46% to 4.34%)/6.13% (95% CI = 5.56% to 6.75%) for Buri Ram. On the year-2 survey, the prevalence among vaccinated grade 10 schoolgirls was 0.57% (95% CI = 0.42% to 0.77%) for Udon Thani and 0.31% (95% CI = 0.21% to 0.47%) for Buri Ram. The 2-year postvaccination crude vaccine effectiveness for the single-dose regimen was estimated at 80.4% (95% CI = 73.9% to 86.9%), and for the 2-dose regimen at 91.9% (95% CI = 88.5% to 95.4%). On the year-4 survey, the prevalence among vaccinated grade 12 schoolgirls was 0.37% (95% CI = 0.25% to 0.56%) for Udon Thani and 0.28% (95% CI = 0.18% to 0.45%) for Buri Ram. Four-year postvaccination crude vaccine effectiveness for the single-dose regimen was estimated at 90.6% (95% CI = 86.6% to 94.6%) and for the 2-dose regimen was estimated at 95.4% (95% CI = 93.2% to 97.6%). All adjustment methods minimally affected vaccine effectiveness for the single-dose and 2-dose regimens. At 4 years after vaccination, the difference in crude vaccine effectiveness between the single-dose and 2-dose regimens was ‒4.79% (95% CI = ‒9.32% to ‒0.25%), meeting the study's noninferiority criteria. CONCLUSIONS:Our study demonstrated that both single-dose and 2-dose HPV vaccination significantly decreased HPV-16/18 point prevalence 2 years and 4 years after vaccination. Crude vaccine effectiveness at 4 years after vaccination was greater than 90% for both the single-dose and 2-dose regimens; the single-dose regimen was not inferior to the 2-dose regimen. These data show that a single dose of HPV vaccine provides high levels of protection when administered to schoolgirls younger than 15 years of age.

The modestly efficacious HIV-1 vaccine regimen (RV144) conferred 31% vaccine efficacy at 3 years following the four-shot immunization series, coupled with rapid waning of putative immune correlates of decreased infection risk. New strategies to increase magnitude and durability of protective immunity are critically needed. The RV305 HIV-1 clinical trial evaluated the immunological impact of a follow-up boost of HIV-1-uninfected RV144 recipients after 6-8 years with RV144 immunogens (ALVAC-HIV alone, AIDSVAX B/E gp120 alone, or ALVAC-HIV + AIDSVAX B/E gp120). Previous reports demonstrated that this regimen elicited higher binding, antibody Fc function, and cellular responses than the primary RV144 regimen. However, the impact of the canarypox viral vector in driving antibody specificity, breadth, durability and function is unknown. We performed a follow-up analysis of humoral responses elicited in RV305 to determine the impact of the different booster immunogens on HIV-1 epitope specificity, antibody subclass, isotype, and Fc effector functions. Importantly, we observed that the ALVAC vaccine component directly contributed to improved breadth, function, and durability of vaccine-elicited antibody responses. Extended boosts in RV305 increased circulating antibody concentration and coverage of heterologous HIV-1 strains by V1V2-specific antibodies above estimated protective levels observed in RV144. Antibody Fc effector functions, specifically antibody-dependent cellular cytotoxicity and phagocytosis, were boosted to higher levels than was achieved in RV144. V1V2 Env IgG3, a correlate of lower HIV-1 risk, was not increased; plasma Env IgA (specifically IgA1), a correlate of increased HIV-1 risk, was elevated. The quality of the circulating polyclonal antibody response changed with each booster immunization. Remarkably, the ALVAC-HIV booster immunogen induced antibody responses post-second boost, indicating that the viral vector immunogen can be utilized to selectively enhance immune correlates of decreased HIV-1 risk. These results reveal a complex dynamic of HIV-1 immunity post-vaccination that may require careful balancing to achieve protective immunity in the vaccinated population. Trial registration: RV305 clinical trial (ClinicalTrials.gov number, NCT01435135). ClinicalTrials.gov Identifier: NCT00223080.