Julia Lynch

Background/Objectives: Cholera remains an important global health problem. Inactivated oral cholera vaccines (OCVs) are essential in the WHO/GTFCC (World Health Organization/Global Task Force on Cholera Control) strategy to end cholera by 2030; however, global supply is insufficient, they require partial cold-chain storage, and their formulation and antigen contents leave room for improvement. We describe here the development and preclinical evaluation of DuoChol OCV, a next-generation thermostable oral vaccine designed to address these gaps. Methods: DuoChol is a lyophilized dry-powder formulation in enteric capsules containing formalin-inactivated Vibrio cholerae O1 El Tor Ogawa and Inaba isogenic bacteria, recombinant cholera toxin B subunit (rCTB), and sucrose as stabilizer. Methods describe the construction of the novel vaccine strains, processes for the preparation and characterization of vaccine components, and the final dry formulation in enteric capsules, and in vitro and in vivo vaccine stability analyses. Results: The newly engineered vaccine strains, together with a high-yield mixed-mode chromatography process for rCTB purification, enabled efficient and cost-effective vaccine production. Stability studies demonstrated complete preservation of O1 LPS and rCTB antigens for at least 21 months across temperatures of 4–40 °C. Moreover, regardless of storage duration or temperature, oral immunization of mice with DuoChol elicited strong serum and mucosal antibacterial and antitoxin responses that were similar to those induced by the licensed Dukoral^® OCV. Conclusions: Its heat stability, practical enteric capsule formulation, and potential for improved efficacy compared to inactivated whole-cell only OCVs support positioning DuoChol as a promising next-generation OCV, suitable for national cholera control programs and particularly advantageous for outbreak response, where rapid deployment and early, robust protection are essential.

Hepatitis E virus (HEV) is a significant public health concern, particularly in resource-limited and conflict-affected settings. While often self-limiting, HEV infection poses severe risks for pregnant women contracted with genotype 1 or 2, leading to high maternal mortality, and can cause chronic infection in immunocompromised individuals. This review examines the epidemiology, clinical manifestations, and vaccine landscape of HEV, highlighting licensed and investigational candidates. We discuss HEV 239 vaccine the only licensed HEV vaccine which has shown high efficacy and cross-genotype protection, leading to approval in China and Pakistan. However, data gaps remain regarding its safety in pregnant women, children, and immunocompromised populations. WHO prequalification is needed for broader global access. We also review the current status of HEV vaccine development, and explore challenges, opportunities, and global policies, including efforts to improve outbreak response in high-risk settings. HEV vaccines are essential for disease control, but unresolved issues limit broader use. Conflicting data on miscarriage risk requires further investigation. Ongoing trials in Pakistan and South Africa will offer key data on safety in pregnancy, immunogenicity in children, and use in people with HIV. WHO prequalification of HEV 239 vaccine is critical to expand access globally.

There is a need for next-generation cholera vaccines that provide high-level and durable protection in young children in cholera-endemic areas. A cholera conjugate vaccine (CCV) is in development to address this need. This vaccine contains the O-specific polysaccharide (OSP) of Vibrio cholerae O1 conjugated via squaric acid chemistry to a recombinant fragment of the tetanus toxin heavy chain (OSP:rTTHc). This vaccine has been shown previously to be immunogenic and protective in mice and found to be safe in a recent preclinical toxicological analysis in rabbits. We took advantage of excess serum samples collected as part of the toxicological study and assessed the immunogenicity of CCV OSP:rTTHc in rabbits. We found that vaccination with CCV induced OSP-, lipopolysaccharide (LPS)-, and rTTHc-specific immune responses in rabbits, that immune responses were functional as assessed by vibriocidal activity, and that immune responses were protective against death in an established virulent challenge assay. CCV OSP:rTTHc immunogenicity in two animal model systems (mice and rabbits) is encouraging and supports further development of this vaccine for evaluation in humans.

Background: Understanding the public health value of a vaccine at an early stage of development helps in valuing and prioritizing the investment needed. Here we present the potential cost-effectiveness of an upcoming 12 valent pneumococcal conjugate vaccine (PCV 12) in the case study country, Thailand. Methods: The cost-effectiveness analysis included a hypothetical scenario of three doses (2 + 1 regimen) PCV12 introduction in the national immunization program of Thailand compared to no PCV, PCV10, and PCV13 among <6 months old from a societal perspective with a lifetime horizon and one-year cycle length. Data from Thailand, as well as assumptions supported by the literature, were used in the analysis. The price of PCV12 was assumed similar to that of PCV10 or PCV13 for GAVI’s eligible countries based on inputs from stakeholder meeting. A one-way sensitivity analysis was conducted using 0.5–1.5 times the base price of PCV12. Results were presented in incremental cost-effectiveness ratio (ICER) in terms of monetary value per quality-adjusted life-year (QALY) gained. Results: Vaccination with PCV12 among a hypothetical cohort of 100,000 Thai children is expected to avert a total of 5358 cases which includes 5 pneumococcal meningitis, 43 pneumococcal bacteremia, 5144 all-cause pneumonia, and 166 all-cause acute otitis media compared to no vaccination. The national PCV12 vaccination program is a cost-saving strategy compared to the other three strategies. The one-way sensitivity analysis showed PCV12 is a cost-saving strategy when 1.5 times the base price of PCV12 was assumed. Conclusions: Within the limitations of hypothetical assumptions and price points incorporated, the study indicates the potential public health value of PCV12 in Thailand.

Human papillomavirus (HPV) is a common infection principally spread through sexual activity. Most HPV infections are asymptomatic and resolve spontaneously. However, persistent infection may progress to cervical cancer. Highly efficacious HPV vaccines have been available since 2006, yet uptake into national programs has been slow in part due to cost. WHO guidelines call for a two-dose (0,6 month) schedule for girls 9–14 years of age. Post-hoc analyses of randomized trials have found high vaccine effectiveness following a single dose of vaccine. In order to provide additional data on the potential impact of single dose HPV vaccination in a real-world setting, we are conducting an effectiveness study among Thai schoolgirls. This is an observational study of a single dose (SD) or two doses (2D) of the bivalent HPV vaccine CERVARIX® (GlaxoSmithKline plc.) administered in a school-based program to 8–9,000 Grade 8 female students in two provinces of Thailand beginning in 2018; one province is assigned the SD, and the other the standard 2D regimen. The reduction in HPV vaccine-type prevalence will be assessed in each province two and four years after vaccination by comparing HPV prevalence in urine samples obtained through cross-sectional surveys of the immunized grade cohort as they age and compared to a historical “baseline” HPV prevalence of same age students.

Although measuring vaccine efficacy through the conventional phase III study design, randomized, double-blinded controlled trial serves as the “gold standard”, effectiveness studies, conducted in the context of a public health program, seek to broaden the understanding of the impact of a vaccine in a real world setting including both individual and population level impacts. Cholera is an acute diarrheal infection caused by the ingestion of food or water contaminated with the bacterium Vibrio cholerae. Since the 1980s, either killed or live oral cholera vaccines (OCVs) have been developed and efficacy and effectiveness studies have been conducted on OCV. Although the results of OCV effectiveness studies sometimes showed outliers, the tendency seen is for effectiveness of the vaccine used in public health settings to be somewhat higher than estimated in randomized controlled trials due to the influence of indirect herd protection. Efficacy and Effectiveness studies both generate important information about the vaccine performance characteristics and its impact when used in real world populations at risk for the disease.

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. 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. 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. 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. The study is registered at ( http://clinicaltrials.gov ). Identifier: NCT02027207 .

Cholera remains a major public health problem in many countries. Poor sanitation and inappropriate clean water supply, insufficient health literacy and community mobilization, absence of national plans and cross-border collaborations are major factors impeding optimal control of cholera in endemic countries. In March 2017, a group of experts from 10 Asian cholera-prone countries that belong to the Initiative against Diarrheal and Enteric Diseases in Africa and Asia (IDEA), together with representatives from the World Health Organization, the US National Institutes of Health, International Vaccine Institute, Agence de médecine préventive, NGOs (Save the Children) and UNICEF, met in Hanoi (Vietnam) to share progress in terms of prevention and control interventions on water, sanitation and hygiene (WASH), surveillance and oral cholera vaccine use. This paper reports on the country situation, gaps identified in terms of cholera prevention and control and strategic interventions to bridge these gaps.