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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.

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.

Abstract Investment in Strep A vaccine R&D is disproportionately low relative to the large burden of Strep A diseases globally. This study presents a novel Strep A vaccine global demand and financial forecast model with estimates of potential global demand and associated revenue and profits for a hypothetical Strep A vaccine as well as a net present value (NPV) analysis of return on capital investments required to develop the vaccine. A positive NPV was calculated for a variety of developer scenarios and target populations, including the global rollout of the vaccine in private and public markets by a multinational pharmaceutical corporation and a staged rollout by a developing country vaccine manufacturer for both infant and child populations. The results suggest there is a viable commercial market for a Strep A vaccine. It is hoped that this study will help to inform industry decision-making and drive increased prioritization of, and investment in, Strep A vaccine research and development.

Abstract Group A Streptococcus causes a wide range of diseases from relatively mild infections including pharyngitis to more severe illnesses such as invasive diseases and rheumatic heart disease (RHD). Our aim is to estimate the cost-effectiveness of a hypothetical Strep A vaccine on multiple disease manifestations at the global-level. Cost-effectiveness analyses were carried out by building on the potential epidemiological impact of vaccines that align with the WHO’s Preferred Product Characteristics for Strep A vaccines. Maximum vaccination costs for a cost-effective vaccination strategy were estimated at the thresholds of 1XGDP per capita and health opportunity costs. The maximum cost per fully vaccinated person for Strep A vaccination to be cost-effective was $385–$489 in high-income countries, $213–$312 in upper-income-income countries, $74–$132 in lower-middle-income countries, and $37–$69 in low-income countries for routine vaccination at birth and 5 years of age respectively. While the threshold costs are sensitive to vaccine characteristics such as efficacy, and waning immunity, a cost-effective Strep A vaccine will lower morbidity and mortality burden in all income settings.

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.

Abstract Considering the lack of existing evidence on economic burden for diseases caused by group A Streptococcus, we estimated the economic burden per episode for selected diseases. Each cost component of direct medical costs (DMCs), direct non-medical costs (DNMCs), and indirect costs (ICs) was separately extrapolated and aggregated to estimate the economic burden per episode by income group as classified by the World Bank. Adjustment factors for DMC and DNMC were generated to overcome related data insufficiencies. To address uncertainty surrounding input parameters, a probabilistic multivariate sensitivity was carried out. The average economic burden per episode ranged from $22 to $392 for pharyngitis, $25 to $2,903 for impetigo, $47 to $2,725 for cellulitis, $662 to $34,330 for invasive and toxin-mediated infections, $231 to $6,332 for acute rheumatic fever (ARF), $449 to $11,717 for rheumatic heart disease (RHD), and $949 to $39,560 for severe RHD across income groups. The economic burden for multiple Group A Streptococcus diseases underscores an urgent need to develop effective prevention strategies including vaccines.

Abstract Recent efforts have re-invigorated the Streptococcus pyogenes (Group A Streptococcus) vaccine development field, though scientific, regulatory and commercial barriers persist, and the vaccine pipeline remains sparse. There is an ongoing need to accelerate all aspects of development to address the large global burden of disease caused by the pathogen. Building on over 100 years of S. pyogenes vaccine development, there are currently eight candidates on a product development track, including four M protein-based candidates and four candidates designed around non-M protein antigens. These candidates have demonstrated proof of concept for protection against S. pyogenes in preclinical models, one has demonstrated safety and immunogenicity in a Phase 1 trial and at least four others are poised to soon enter clinical trials. To maintain momentum, the Strep A Vaccine Global Consortium (SAVAC) was established to bring together experts to accelerate global S. pyogenes vaccine development. This article highlights the past, present and future of S. pyogenes vaccine development and emphasizes key priorities, and the role of SAVAC, in advancing the field.

Abstract Understanding immunity in humans to Group A Streptococcus (Strep A) is critical for the development of successful vaccines to prevent the morbidity and mortality attributed to Strep A infections. Despite decades of effort, no licensed vaccine against Strep A exists and immune correlates of protection are lacking; a major impediment to vaccine development. In the absence of a vaccine, we can take cues from the development of natural immunity to Strep A in humans to identify immune correlates of protection. The age stratification of incidence of acute Strep A infections, peaking in young children and waning in early adulthood, coincides with the development of specific immune responses. Therefore, understanding the immune mechanisms involved in natural protection from acute Strep A infection is critical to identifying immune correlates to inform vaccine development. This perspective summarises the findings from natural infection studies, existing assays of immunity to Strep A, and highlights the gaps in knowledge to guide the development of Strep A vaccines and associated correlates of protection.

Climate change represents an unprecedented threat to humanity and will be the ultimate challenge of the 21st century. As a public health consequence, the World Health Organization estimates an additional 250,000 deaths annually by 2030, with resource-poor countries being predominantly affected. Although climate change’s direct and indirect consequences on human health are manifold and far from fully explored, a growing body of evidence demonstrates its potential to exacerbate the frequency and spread of transmissible infectious diseases. Effective, high-impact mitigation measures are critical in combating this global crisis. While vaccines and vaccination are among the most cost-effective public health interventions, they have yet to be established as a major strategy in climate change-related health effect mitigation. In this narrative review, we synthesize the available evidence on the effect of climate change on vaccine-preventable diseases. This review examines the direct effect of climate change on water-related diseases such as cholera and other enteropathogens, helminthic infections and leptospirosis. It also explores the effects of rising temperatures on vector-borne diseases like dengue, chikungunya, and malaria, as well as the impact of temperature and humidity on airborne diseases like influenza and respiratory syncytial virus infection. Recent advances in global vaccine development facilitate the use of vaccines and vaccination as a mitigation strategy in the agenda against climate change consequences. A focused evaluation of vaccine research and development, funding, and distribution related to climate change is required.

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.

BackgroundLeptospirosis, a prevalent zoonotic disease with One Health priority and a disease of poverty, lacks global economic burden estimates. This study aims to determine the global, regional, and country-level cost of leptospirosis due to loss of productivity.Methodology/principal findingsThe cost of leptospirosis due to loss of productivity (referred to as productivity cost hereafter) was estimated by converting the disability-adjusted life years (DALYs) lost due to leptospirosis to a monetary value using the per capita gross domestic product (GDP). The country-specific DALYs lost were obtained from the global burden of leptospirosis study published previously. Non-health GDP per capita (GDP- per capita health expenditure) was used for the cost conversion of DALYs. Country-specific GDP and health expenditure data were obtained from the World Bank data repositories. Estimates were done using both nominal and international dollars. The estimated global productivity cost of leptospirosis in 2019 was Int$ 29.3 billion, with low and high estimates ranging from Int$ 11.6 billion to 52.3 billion. China (Int$ 4.8 billion), India (Int$ 4.6 billion), Indonesia (Int$ 2.8 billion), Sri Lanka (Int$ 2.1 billion), and the United States (Int$ 1.3 billion) had the highest productivity cost due to leptospirosis. Eight out of 10 countries with the highest burden were in the Asia-Pacific region. In addition, lower-middle-income countries had an annual productivity cost of Int$ 13.8 billion, indicating that the disease is poverty-related.ConclusionAlthough significant, the cost estimate due to loss of productivity is merely a fraction of the overall economic burden of this disease, which also includes other direct, indirect, and intangible costs. The existing partial estimates of the different components of economic cost suggest a profound economic burden that demands the inclusion of leptospirosis in the global health agenda for comprehensive disease control and prevention efforts, including vaccine development.

Although significant progress has been made in achieving goals for COVID-19 vaccine access, the quest for equity and justice remains an unfinished agenda. Vaccine nationalism has prompted calls for new approaches to achieve equitable access and justice not only for vaccines but also for vaccination. This includes ensuring country and community participation in global discussions and that local needs to strengthen health systems, address issues related to social determinants of health, build trust and leverage acceptance to vaccines, are addressed. Regional vaccine technology and manufacturing hubs are promising approaches to address access challenges and must be integrated with efforts to ensure demand. The current situation underlines the need for access, demand and system strengthening to be addressed along with local priorities for justice to be achieved. Innovations to improve accountability and leverage existing platforms are also needed. Sustained political will and investment is required to ensure ongoing production of non-pandemic vaccines and sustained demand, particularly when perceived threat of disease appears to be waning. Several recommendations are made to govern towards justice including codesigning the path forward with low-income and middle-income countries; establishing stronger accountability measures; establishing dedicated groups to engage with countries and manufacturing hubs to ensure that the affordable supply and predictable demand are in balance; addressing country needs for health system strengthening through leveraging existing health and development platforms and delivering on product presentations informed by country needs. Even if difficult, we must converge on a definition of justice well in advance of the next pandemic.

Through the experiences gained by accelerating new vaccines for both Ebola virus infection and COVID-19 in a public health emergency, vaccine development has benefited from a ‘multiple shots on goal’ approach to new vaccine targets. This approach embraces simultaneous development of candidates with differing technologies, including, when feasible, vesicular stomatitis virus or adenovirus vectors, messenger RNA (mRNA), whole inactivated virus, nanoparticle and recombinant protein technologies, which led to multiple effective COVID-19 vaccines. The challenge of COVID-19 vaccine inequity, as COVID-19 spread globally, created a situation where cutting-edge mRNA technologies were preferentially supplied by multinational pharmaceutical companies to high-income countries while low and middle-income countries (LMICs) were pushed to the back of the queue and relied more heavily on adenoviral vector, inactivated virus and recombinant protein vaccines. To prevent this from occurring in future pandemics, it is essential to expand the scale-up capacity for both traditional and new vaccine technologies at individual or simultaneous hubs in LMICs. In parallel, a process of tech transfer of new technologies to LMIC producers needs to be facilitated and funded, while building LMIC national regulatory capacity, with the aim of several reaching ‘stringent regulator’ status. Access to doses is an essential start but is not sufficient, as healthcare infrastructure for vaccination and combating dangerous antivaccine programmes both require support. Finally, there is urgency to establish an international framework through a United Nations Pandemic Treaty to promote, support and harmonise a more robust, coordinated and effective global response.

The COVID-19 pandemic triggered a sense of vulnerability and urgency that led to concerted actions by governments, funders, regulators and industry to overcome traditional challenges for the development of vaccine candidates and to reach authorisation. Unprecedented financial investments, massive demand, accelerated clinical development and regulatory reviews were among the key factors that contributed to accelerating the development and approval of COVID-19 vaccines. The rapid development of COVID-19 vaccines benefited of previous scientific innovations such as mRNA and recombinant vectors and proteins. This has created a new era of vaccinology, with powerful platform technologies and a new model for vaccine development. These lessons learnt highlight the need of strong leadership, to bring together governments, global health organisations, manufacturers, scientists, private sector, civil society and philanthropy, to generate innovative, fair and equitable access mechanisms to COVID-19 vaccines for populations worldwide and to build a more efficient and effective vaccine ecosystem to prepare for other pandemics that may emerge. With a longer-term view, new vaccines must be developed with incentives to build expertise for manufacturing that can be leveraged for low/middle-income countries and other markets to ensure equity in innovation, access and delivery. The creation of vaccine manufacturing hubs with appropriate and sustained training, in particular in Africa, is certainly the way of the future to a new public health era to safeguard the health and economic security of the continent and guarantee vaccine security and access, with however the need for such capacity to be sustained in the interpandemic period.

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.

# Background Verbal autopsy can play a key crucial to identify significant causes of death in a developing country like Bangladesh where post-death pathological or forensic examination is not common. Single-dose Cholera Vaccination in Bangladesh (SCVB) was an individually randomized, placebo-controlled, double-blind study where verbal autopsy had been conducted for the participants who died within three months of receiving study agents This study aim was to determine the major causes of death through a verbal autopsy in a defined urban population. # Methods The trial was conducted in urban slums of Dhaka among persons aged one year and older. A census was carried out bi-annually in the study area (Mirpur) including collecting death information from every household. Screening data on death was matched with the vaccination database to confirm whether the participants received the investigational products (IP) or not. The trained physician conducted a verbal autopsy usually within 7 days of notification. # Results The screening period for verbal autopsy was from May 22 to July 18, 2014. Among 250 detected deaths, 99 received study agents (50 vaccines and 49 placeboes). The Verbal autopsy could not be completed for 10 deaths due to the unavailability of a next of kin respondent. Of the total of 240 verbal autopsies performed, 217 were in adults aged 18 years and above, 6 in 5-17 years of age, and rest were ≤ 5 years. The Most common causes of death were non-communicable diseases. 163 deaths occurred at home, 59 in a hospital and others died in different places. No significant difference in cause of death among vaccine and placebo group was found from this analysis. # Conclusions Verbal autopsies usefully identified probable causes of death in participants in an oral cholera vaccine trial. The findings highlight that in this urban slum, noncommunicable diseases account for most of deaths.

Cholera remains a public health threat among the least privileged populations and regions affected by conflicts and natural disasters. Together with Water, Sanitation and Hygiene practices, use of oral cholera vaccines (OCVs) is a key tool to prevent cholera. Bivalent whole-cell killed OCVs have been extensively used worldwide and found effective in protecting populations against cholera in endemic and outbreak settings. No cholera vaccine had been available for United States (US) travelers at risk for decades until 2016 when CVD 103-HgR (Vaxchora™), an oral live attenuated vaccine, was licensed by the US FDA. A single dose of Vaxchora™ protected US volunteers against experimental challenge 10 days and 3 months after vaccination. However, use of Vaxchora™ poses several challenges in resource poor settings as it requires reconstitution, is age-restricted to 18 to 64 years, has no data in populations endemic for cholera, and faces challenges related to cold chain and cost.

Introduction: Given the complexities of HIV infection and the HIV genetic heterogeneity, a successful HIV vaccine should elicit broad adaptive and innate immune responses. Vaccine prime-boost platforms may achieve this goal. Several factors including selection of antigen, type of vector, delivery route, dose, adjuvant, boosting regimen, order of vector injection, and intervals between vaccinations influence the outcome. Areas covered: We reviewed the literature on the latest findings of the various prime-boost HIV vaccine clinical trials, with particular emphasis on the most advanced and promising strategies. Expert opinion: Data suggest that heterologous may be better than homologous prime-boost regimens for protection. The most advanced strategies to have reached efficacy trials use either canarypox vector (ALVAC) boosted by adjuvanted gp120 protein or adenovirus (Ad26) vector expressing mosaic antigens boosted by gp140 protein. DNA prime and vectors and/or protein boost regimens are at less advanced development stage. These regimens, while imperfect (efficacy ≥50%), could contribute substantially to the control of HIV epidemics as a part of a comprehensive HIV prevention program. To ensure prompt vaccine access in populations with the greatest need, attention should be given to post-efficacy activities necessary to achieve appropriate uptake and implementation of effective vaccines.

Abstract Background Cholera increases the risk of harmful effects on foetuses. We prospectively followed pregnant women unaware of their pregnancy status who received a study agent in a clinical trial evaluating the association between exposure to an oral cholera vaccine (OCV) and foetal survival. Methods Study participants were selected from a randomized placebo-controlled trial conducted in Dhaka, Bangladesh. The vaccination campaign was conducted between January 10 and February 4, 2014. We enrolled women who were exposed to an OCV or placebo during pregnancy (Cohort 1) and women who were pregnant after the vaccination was completed (Cohort 2). Our primary endpoint was pregnancy loss (spontaneous miscarriage or stillbirth), and the secondary endpoints were preterm delivery and low birth weight. We employed a log-binomial regression to calculate the relative risk of having adverse outcomes among OCV recipients compared to that among placebo recipients. Result There were 231 OCV and 234 placebo recipients in Cohort 1 and 277 OCV and 299 placebo recipients in Cohort 2. In Cohort 1, the incidence of pregnancy loss was 113/1000 and 115/1000 among OCV and placebo recipients, respectively. The adjusted relative risk for pregnancy loss was 0.97 (95% CI: 0.58–1.61; p = 0.91) in Cohort 1. We did not observe any variation in the risk of pregnancy loss between the two cohorts. The risks for preterm delivery and low birth weight were not significantly different between the groups in both cohorts. Conclusions Our study provides additional evidence that exposure to an OCV during pregnancy does not increase the risk of pregnancy loss, preterm delivery, or low birth weight, suggesting that pregnant women in cholera-affected regions should not be excluded in a mass vaccination campaign. Trial registration The study is registered at (http://clinicaltrials.gov). Identifier: NCT02027207.

Background: Typhoid causes significant mortality among young children in resource-limited settings. Conjugate typhoid vaccines could significantly reduce typhoid-related child deaths, but only one WHO-prequalified typhoid conjugate vaccine exists for young children. To address this gap, we investigated the safety, immunogenicity and dose-scheduling of Vi-DT typhoid conjugate vaccine among children aged 6-23 months. Methods: In this single center, observer blind, phase II trial, participants were randomly assigned (2:2:1) to receive one or two doses of Vi-DT or comparator vaccine. Anti-Vi IgG titer and geometric mean titers (GMT) were determined at 0, 4, 24 and 28 weeks. Data were analyzed using per-protocol and immunogenicity (a subset of intention-to-treat analysis) sets. The trial is registered with ClinicalTrials.gov (NCT03527355). Findings: Between April and July 2018, 285 children were randomized; 114 received one or two doses of Vi-DT while 57 received comparator. 277 completed the study follow-up per protocol; 112 and 110 from single- and two-dose Vi-DT schedules, respectively and 55 from the placebo group were included in the per protocol analysis. Safety profile is satisfactory. Thirteen serious adverse events were reported during the 28-week follow-up, none of which were related to Vi-DT. The seroconversion rate four weeks after the first dose was 100% (95% CI 98·3-100) in Vi-DT recipients and 7·0% (95% CI 2·8-16·7) in comparator recipients (p

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is an emerging pathogen with the potential to pose a threat to global public health. Sporadic cases and outbreaks continue to be reported in the Middle East, and case fatality rates remain high at approximately 36% globally. No specific preventive or therapeutic countermeasures currently exist. A safe and effective vaccine could play an important role in protecting against the threat from MERS-CoV. This review discusses human vaccine candidates currently under development, and explores viral characteristics, molecular epidemiology and immunology relevant to MERS-CoV vaccine development. At present, a DNA vaccine candidate has begun a human clinical trial, while two vector-based candidates will very soon begin human trials. Protein-based vaccines are still at pre-clinical stage. Challenges to successful development include incomplete understanding of viral transmission, pathogenesis and immune response (in particular at the mucosal level), no optimal animal challenge models, lack of standardized immunological assays, and insufficient sustainable funding.

IntroductionThere is a high global incidence of typhoid fever, with an annual mortality rate of 200,000 deaths. Typhoid fever also affects younger children, particularly in resource-limited settings in endemic countries. Typhoid vaccination is an important prevention tool against typhoid fever. However, the available polysaccharide typhoid vaccines are not recommended for children under 2 years of age. A new typhoid conjugate Vi-diphtheria toxoid (Vi-DT) vaccine has been developed for infant immunization. We aimed to define the safety and immunogenicity of the Vi-DT vaccine among adults and children in Indonesia.MethodsAn observational, blinded, comparative, randomized, phase I safety study in two age de-escalating cohorts was conducted in East Jakarta, Indonesia, from April 2017 to February 2018. We enrolled 100 healthy subjects in 2 age groups: adults and children (18-40 and 2-5 years old). These groups were randomized into study groups (Vi-DT vaccine), and comparator groups (Vi-polysaccharide (Vi-PS) vaccine and another additional vaccine) which was administered in 4 weeks apart. Subjects were followed up to six months.ResultOne hundred healthy adults and children subjects completed the study. The Vi-DT and Vi-PS vaccines showed no difference in terms of intensity of any immediate local and systemic events within 30 minutes post-vaccination. Overall, pain was the most common local reaction, and muscle pain was the most common systemic reaction in the first 72 hours. No serious adverse events were deemed related to vaccine administration. The first and second doses of the Vi-DT vaccine induced seroconversion and higher geometric mean titers (GMT) in all subjects compared to that of baseline. However, in terms of GMT, the second dose of Vi-DT did not induce a booster response.ConclusionThe Vi-DT vaccine is safe and immunogenic in adults and children older than two years. A single dose of the vaccine is able to produce seroconversion and high GMT in all individuals.

The US military has been a leading proponent of vaccine development since its founding. General George Washington ordered the entire American army to be variolated against smallpox after recognizing the serious threat that it posed to military operations. He did this on the recommendation from Dr. John Morgan, the physician-in-chief of the American army, who wrote a treatise on variolation in 1776. Although cases of smallpox still occurred, they were far fewer than expected, and it is believed that the vaccination program contributed to victory in the War of Independence. Effective military force requires personnel who are healthy and combat ready for worldwide deployment. Given the geography of US military operations, military personnel should also be protected against diseases that are endemic in potential areas of conflict. For this reason, and unknown to many, the US military has strongly supported vaccine research and development. Four categories of communicable infectious diseases threaten military personnel: (1) diseases that spread easily in densely populated areas (respiratory and dysenteric diseases); (2) vector-borne diseases (disease carried by mosquitoes and other insects); (3) sexually transmitted diseases (hepatitis, HIV, and gonorrhea); and (4) diseases associated with biological warfare. For each category, the US military has supported research that has provided the basis for many of the vaccines available today. Although preventive measures and the development of drugs have provided some relief from the burden of malaria, dengue, and HIV, the US military continues to fund research and development of prophylactic vaccines that will contribute to force health protection and global health. In the past few years, newly recognized infections with Zika, severe acute respiratory syndrome, Middle East respiratory syndrome viruses have pushed the US military to fund research and fast track clinical trials to quickly and effectively develop vaccines for emerging diseases. With US military personnel present in every region of the globe, one of the most cost-effective ways to maintain military effectiveness is to develop vaccines against prioritized threats to military members’ health.

Sexual transmission is the principal driver of the human immunodeficiency virus (HIV) pandemic. Understanding HIV vaccine-induced immune responses at mucosal surfaces can generate hypotheses regarding mechanisms of protection, and may influence vaccine development. The RV144 (ClinicalTrials.gov NCT00223080) efficacy trial showed protection against HIV infections but mucosal samples were not collected, therefore, the contribution of mucosal antibodies to preventing HIV-1 acquisition is unknown. Here, we report the generation, magnitude and persistence of antibody responses to recombinant gp120 envelope and antigens including variable one and two loop scaffold antigens (gp70V1V2) previously shown to correlate with risk in RV144. We evaluated antibody responses to gp120 A244gD and gp70V1V2 92TH023 (both CRF01_AE) and Case A2 (subtype B) in cervico-vaginal mucus (CVM), seminal plasma (SP) and rectal secretions (RS) from HIV-uninfected RV144 vaccine recipients, who were randomized to receive two late boosts of ALVAC-HIV/AIDSVAX®B/E, AIDSVAX®B/E, or ALVAC-HIV alone at 0 and 6 months. Late vaccine boosting increased IgG geometric mean titers (GMT) to gp120 A244gD in AIDSVAX®B/E and ALVAC-HIV/AIDSVAX®B/E CVM (28 and 17 fold, respectively), followed by SP and RS. IgG to gp70V1V2 92TH023 increased in AIDSVAX®B/E and ALVAC-HIV/AIDSVAX®B/E CVM (11-17 fold) and SP (2 fold) two weeks post first boost. IgG to Case A2 was only detected in AIDSVAX®B/E and ALVAC-HIV/AIDSVAX®B/E CVM. Mucosal IgG to gp120 A244gD (CVM, SP, RS), gp70V1V2 92TH023 (CVM, SP), and Case A2 (CVM) correlated with plasma IgG levels (p

Recent advances in HIV vaccine development along with a better understanding of the immune correlates of risk have emerged from the RV144 efficacy trial conducted in Thailand. Epidemiological data suggest that CRF01_AE is still predominant in South-East Asia and is spreading in China with a growing number of circulating recombinant forms due to increasing human contact, particularly in large urban centers, tourist locations and in sites of common infrastructure. A vaccine countering CRF01_AE is a priority for the region. An Asia HIV vaccine against expanding B/E or BCE recombinant forms should be actively pursued. A major challenge that remains is the conduct of efficacy trials in heterosexual populations in this region. Men who have sex with men represent the main target population for future efficacy trials in Asia. Coupling HIV vaccines with other prevention modalities in efficacy trials might also be envisaged. These new avenues will only be made possible through the conduct of large-scale efficacy trials, interdisciplinary teams, international collaborations, and strong political and community commitments.

The canary pox vector and gp120 vaccine (ALVAC-HIV and AIDSVAX B/E gp120) in the RV144 HIV-1 vaccine trial conferred an estimated 31% vaccine efficacy. Although the vaccine Env AE.A244 gp120 is antigenic for the unmutated common ancestor of V1V2 broadly neutralizing antibody (bnAbs), no plasma bnAb activity was induced. The RV305 (NCT01435135) HIV-1 clinical trial was a placebo-controlled randomized double-blinded study that assessed the safety and efficacy of vaccine boosting on B cell repertoires. HIV-1-uninfected RV144 vaccine recipients were reimmunized 6-8 years later with AIDSVAX B/E gp120 alone, ALVAC-HIV alone, or a combination of ALVAC-HIV and AIDSVAX B/E gp120 in the RV305 trial. Env-specific post-RV144 and RV305 boost memory B cell VH mutation frequencies increased from 2.9% post-RV144 to 6.7% post-RV305. The vaccine was well tolerated with no adverse events reports. While post-boost plasma did not have bnAb activity, the vaccine boosts expanded a pool of envelope CD4 binding site (bs)-reactive memory B cells with long third heavy chain complementarity determining regions (HCDR3) whose germline precursors and affinity matured B cell clonal lineage members neutralized the HIV-1 CRF01 AE tier 2 (difficult to neutralize) primary isolate, CNE8. Electron microscopy of two of these antibodies bound with near-native gp140 trimers showed that they recognized an open conformation of the Env trimer. Although late boosting of RV144 vaccinees expanded a novel pool of neutralizing B cell clonal lineages, we hypothesize that boosts with stably closed trimers would be necessary to elicit antibodies with greater breadth of tier 2 HIV-1 strains. TRIAL REGISTRATION:ClinicalTrials.gov NCT01435135.

BACKGROUND:In the HIV-1 vaccine trial RV144, ALVAC-HIV prime with an AIDSVAX® B/E boost reduced HIV-1 acquisition by 31% at 42 months post first vaccination. The bivalent AIDSVAX® B/E vaccine contains two gp120 envelope glycoproteins, one from the subtype B HIV-1 MN isolate and one from the subtype CRF01_AE A244 isolate. Each envelope glycoprotein harbors a highly conserved 27-amino acid HSV-1 glycoprotein D (gD) tag sequence that shares 93% sequence identity with the HSV-2 gD sequence. We assessed whether vaccine-induced anti-gD antibodies protected females against HSV-2 acquisition in RV144. METHODS:Of the women enrolled in RV144, 777 vaccine and 807 placebo recipients were eligible and randomly selected according to their pre-vaccination HSV-1 and HSV-2 serostatus for analysis. Immunoglobulin G (IgG) and IgA responses to gD were determined by a binding antibody multiplex assay and HSV-2 serostatus was determined by Western blot analysis. Ninety-three percent and 75% of the vaccine recipients had anti-gD IgG and IgA responses two weeks post last vaccination, respectively. There was no evidence of reduction in HSV-2 infection by vaccination compared to placebo recipients over 78 weeks of follow-up. The annual incidence of HSV-2 infection in individuals who were HSV-2 negative at baseline or HSV-1 positive and HSV-2 indeterminate at baseline were 4.38/100 person-years (py) and 3.28/100 py in the vaccine and placebo groups, respectively. Baseline HSV-1 status did not affect subsequent HSV-2 acquisition. Specifically, the estimated odds ratio of HSV-2 infection by Week 78 for female placebo recipients who were baseline HSV-1 positive (n = 422) vs. negative (n = 1120) was 1.14 [95% confidence interval 0.66 to 1.94, p = 0.64)]. No evidence of reduction in the incidence of HSV-2 infection by vaccination was detected. CONCLUSIONS:AIDSVAX® B/E containing gD did not confer protection from HSV-2 acquisition in HSV-2 seronegative women, despite eliciting anti-gD serum antibodies.

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.

Middle East respiratory syndrome (MERS) remains a serious international public health threat. With the goal of accelerating the development of countermeasures against MERS coronavirus (MERS-CoV), funding agencies, nongovernmental organizations, and researchers across the world assembled in Riyadh, Saudi Arabia, on November 14–15, 2015, to discuss vaccine development challenges. The meeting was spearheaded by the Saudi Ministry of Health and co-organized by the International Vaccine Institute, South Korea. Accelerating the development of a preventive vaccine requires a better understanding of MERS epidemiology, transmission, and pathogenesis in humans and animals. A combination of rodent and nonhuman primate models should be considered in evaluating and developing preventive and therapeutic vaccine candidates. Dromedary camels should be considered for the development of veterinary vaccines. Several vaccine technology platforms targeting the MERS-CoV spike protein were discussed. Mechanisms to maximize investment, provide robust data, and affect public health are urgently needed.

RV144 was a community-based HIV vaccine efficacy trial conducted in HIV-uninfected adults in Thailand, where dengue virus continues to cause a large number of infections every year. We attempted to document the accuracy of clinically diagnosed dengue episodes reported as serious adverse events (SAEs) and adverse events (AEs) and examine whether dengue serology would support the clinical diagnosis. Subjects without a clinical dengue diagnosis but with an infection or idiopathic fever were selected as a control population. Dengue serology was performed by hemagglutination inhibition on plasma samples. A total of 124 clinical dengue episodes were reported (103 SAEs and 21 AEs). Overall 82.6% of the clinically diagnosed dengue episodes were supported by a positive dengue serology: 71.4% of the AEs and 85.0% of the SAEs. Of the 100 subjects with both clinical dengue and positive serology, all presented with fever, 83% with leucopenia, 54% with thrombocytopenia, and 27% with hemorrhagic symptoms. All episodes resolved spontaneously without sequellae. Only two of 15 subjects with a negative serology presented with fever. The sensitivity and specificity of clinical dengue diagnosis were 90.9% and 74.4%, respectively, when compared to the control population, and with a positive predictive value of 82.6% and negative predictive value of 84.7% when compared to dengue serology. Clinical diagnosis of dengue is an accurate method of dengue diagnosis in adults in Thailand. Large-scale clinical trials offer the opportunity to systematically study infectious diseases such as dengue and other infections that may occur during the trial.

Mucosal Th17 cells play an important role in maintaining gut epithelium integrity and thus prevent microbial translocation. Chronic HIV infection is characterized by mucosal Th17 cell depletion, microbial translocation and subsequent immune-activation, which remain elevated despite antiretroviral therapy (ART) correlating with increased mortality. However, when Th17 depletion occurs following HIV infection is unknown. We analyzed mucosal Th17 cells in 42 acute HIV infection (AHI) subjects (Fiebig (F) stage I-V) with a median duration of infection of 16 days and the short-term impact of early initiation of ART. Th17 cells were defined as IL-17+ CD4+ T cells and their function was assessed by the co-expression of IL-22, IL-2 and IFNγ. While intact during FI/II, depletion of mucosal Th17 cell numbers and function was observed during FIII correlating with local and systemic markers of immune-activation. ART initiated at FI/II prevented loss of Th17 cell numbers and function, while initiation at FIII restored Th17 cell numbers but not their polyfunctionality. Furthermore, early initiation of ART in FI/II fully reversed the initially observed mucosal and systemic immune-activation. In contrast, patients treated later during AHI maintained elevated mucosal and systemic CD8+ T-cell activation post initiation of ART. These data support a loss of Th17 cells at early stages of acute HIV infection, and highlight that studies of ART initiation during early AHI should be further explored to assess the underlying mechanism of mucosal Th17 function preservation.

A correlation between in vivo and in vitro virus control mediated by CD8+ T-cell populations has been demonstrated by CD8 T-cell-mediated inhibition of HIV-1 and SIV replication in vitro in peripheral blood mononuclear cells (PBMCs) from infected humans and non-human primates (NHPs), respectively. Here, the breadth and specificity of T-cell responses induced following vaccination with replication-defective adenovirus serotype 35 (Ad35) vectors containing a fusion protein of Gag, reverse transcriptase (RT), Integrase (Int) and Nef (Ad35-GRIN) and Env (Ad35-ENV), derived from HIV-1 subtype A isolates, was assessed in 25 individuals. The vaccine induced responses to a median of 4 epitopes per vaccinee. We correlated the CD8 responses to conserved vs. variable regions with the ability to inhibit a panel of 7 HIV-1 isolates representing multiple clades in a virus inhibition assay (VIA). The results indicate that targeting immunodominant responses to highly conserved regions of the HIV-1 proteome may result in an increased ability to inhibit multiple clades of HIV-1 in vitro. The data further validate the use of the VIA to screen and select future HIV vaccine candidates. Moreover, our data suggest that future T cell-focused vaccine design should aim to induce immunodominant responses to highly conserved regions of the virus.

STUDY DESIGN: A randomized, double-blind, placebo controlled phase I trial. METHODS: The trial was conducted in 32 HIV-uninfected healthy volunteers to assess the safety and immunogenicity of prime-boost vaccination regimens with either 2 doses of ADVAX, a DNA vaccine containing Chinese HIV-1 subtype C env gp160, gag, pol and nef/tat genes, as a prime and 2 doses of TBC-M4, a recombinant MVA encoding Indian HIV-1 subtype C env gp160, gag, RT, rev, tat, and nef genes, as a boost in Group A or 3 doses of TBC-M4 alone in Group B participants. Out of 16 participants in each group, 12 received vaccine candidates and 4 received placebos. RESULTS: Both vaccine regimens were found to be generally safe and well tolerated. The breadth of anti-HIV binding antibodies and the titres of anti-HIV neutralizing antibodies were significantly higher (p

We conducted a phase I, randomized, double-blind, placebo-controlled trial to assess the safety and immunogenicity of escalating doses of two recombinant replication defective adenovirus serotype 35 (Ad35) vectors containing gag, reverse transcriptase, integrase and nef (Ad35-GRIN) and env (Ad35-ENV), both derived from HIV-1 subtype A isolates. The trial enrolled 56 healthy HIV-uninfected adults.Ad35-GRIN/ENV (Ad35-GRIN and Ad35-ENV mixed in the same vial in equal proportions) or Ad35-GRIN was administered intramuscularly at 0 and 6 months. Participants were randomized to receive either vaccine or placebo (10/4 per group, respectively) within one of four dosage groups: Ad35-GRIN/ENV 2×10(9) (A), 2×10(10) (B), 2×10(11) (C), or Ad35-GRIN 1×10(10) (D) viral particles.No vaccine-related serious adverse event was reported. Reactogenicity events reported were dose-dependent, mostly mild or moderate, some severe in Group C volunteers, all transient and resolving spontaneously. IFN-γ ELISPOT responses to any vaccine antigen were detected in 50, 56, 70 and 90% after the first vaccination, and in 75, 100, 88 and 86% of Groups A-D vaccine recipients after the second vaccination, respectively. The median spot forming cells (SFC) per 10(6) PBMC to any antigen was 78-139 across Groups A-C and 158-174 in Group D, after each of the vaccinations with a maximum of 2991 SFC. Four to five HIV proteins were commonly recognized across all the groups and over multiple timepoints. CD4+ and CD8+ T-cell responses were polyfunctional. Env antibodies were detected in all Group A-C vaccinees and Gag antibodies in most vaccinees after the second immunization. Ad35 neutralizing titers remained low after the second vaccination.Ad35-GRIN/ENV reactogenicity was dose-related. HIV-specific cellular and humoral responses were seen in the majority of volunteers immunized with Ad35-GRIN/ENV or Ad35-GRIN and increased after the second vaccination. T-cell responses were broad and polyfunctional.ClinicalTrials.gov NCT00851383.

We characterized prime-boost vaccine regimens using heterologous and homologous vector and gene inserts. Heterologous regimens offer a promising approach that focuses the cell-mediated immune response on the insert and away from vector-dominated responses. Ad35-GRIN/ENV (Ad35-GE) vaccine is comprised of two vectors containing sequences from HIV-1 subtype A gag, rt, int, nef (Ad35-GRIN) and env (Ad35-ENV). MVA-CMDR (MVA-C), MVA-KEA (MVA-K) and MVA-TZC (MVA-T) vaccines contain gag, env and pol genes from HIV-1 subtypes CRF01_AE, A and C, respectively. Balb/c mice were immunized with different heterologous and homologous vector and insert prime-boost combinations. HIV and vector-specific immune responses were quantified post-boost vaccination. Gag-specific IFN-γ ELISPOT, intracellular cytokine staining (ICS) (CD107a, IFN-γ, TNF-α and IL-2), pentamer staining and T-cell phenotyping were used to differentiate responses to inserts and vectors. Ad35-GE prime followed by boost with any of the recombinant MVA constructs (rMVA) induced CD8+ Gag-specific responses superior to Ad35-GE-Ad35-GE or rMVA-rMVA prime-boost combinations. Notably, there was a shift toward insert-focus responses using heterologous vector prime-boost regimens. Gag-specific central and effector memory T cells were generated more rapidly and in greater numbers in the heterologous compared to the homologous prime-boost regimens. These results suggest that heterologous prime-boost vaccination regimens enhance immunity by increasing the magnitude, onset and multifunctionality of the insert-specific cell-mediated immune response compared to homologous vaccination regimens. This study supports the rationale for testing heterologous prime-boost regimens in humans.

A prime-boost vaccination regimen with ALVAC-HIV (vCP1521) administered intramuscularly at 0, 4, 12, and 24 weeks and gp120 AIDSVAX B/E at 12 and 24 weeks demonstrated modest efficacy of 31.2% for prevention of HIV acquisition in HIV-uninfected adults participating in a community-based efficacy trial in Thailand.Reactogenicity was recorded for 3 days following vaccination. Adverse events were monitored every 6 months for 3.5 years, during which pregnancy outcomes were recorded. Of the 16,402 volunteers, 69% of the participants reported an adverse event any time after the first dose. Only 32.9% experienced an AE within 30 days following any vaccination. Overall adverse event rates and attribution of relatedness did not differ between groups. The frequency of serious adverse events was similar in vaccine (14.3%) and placebo (14.9%) recipients (p = 0.33). None of the 160 deaths (85 in vaccine and 75 in placebo recipients, p = 0.43) was assessed as related to vaccine. The most common cause of death was trauma or traffic accident. Approximately 30% of female participants reported a pregnancy during the study. Abnormal pregnancy outcomes were experienced in 17.1% of vaccine and 14.6% (p = 0.13) of placebo recipients. When the conception occurred within 3 months (estimated) of a vaccination, the majority of these abnormal outcomes were spontaneous or elective abortions among 22.2% and 15.3% of vaccine and placebo pregnant recipients, respectively (p = 0.08). Local reactions occurred in 88.0% of vaccine and 61.0% of placebo recipients (p