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Cholera remains a major global public health problem that is primarily linked to insufficient access to safe water and proper sanitation. Oral Cholera Vaccine (OCV) has been recommended as an additional public health tool along with WASH in cholera endemic countries and in areas at risk for outbreaks. The new generation OCV is safe and offers good protection in older children and adults while limited protection in younger children less than five years of age has been observed. The combination of direct vaccine protection and vaccine herd immunity effects makes OCV highly cost-effective and, therefore, attractive for use in developing countries. Additionally, in recent studies OCV was safe in pregnant women, supporting its use in pregnant women in cholera endemic countries. However, knowledge need to be developed for current vaccines for their prolonged duration of protection and vaccines need improvements for better immune response in younger children. A single dose vaccination regimen would be more cost-effective and easier to deliver. Recent approaches have focused on designing genetically attenuated cholera strains for use in single-dose cholera vaccines. The global demand for OCV has been boosted by the WHO recommendation to use OCV and is driven largely by epidemics and outbreaks and has been increasing due to the availability of cheaper easy-to-use vaccines, feasibility of mass OCV vaccination campaigns, demonstration of protection to underserved population in precarious situations, and vaccine costs being borne by Gavi (Vaccine Alliance). For rapid access in emergency and equitable distribution of OCV in cholera-endemic low-income countries, a global OCV stockpile was established in 2013 with support from the Global Alliance for Vaccines and Immunization. The three WHO-prequalified vaccines are Dukoral®, Shanchol™, Euvichol® (and Euvichol® Plus presentation), the latter two being included in the stockpile.

Background Leptospirosis, 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 findings The 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. Conclusion Although 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.

Examination of the vaccine strategies and technical platforms used for the COVID-19 pandemic in the context of those used for previous emerging and reemerging infectious diseases and pandemics may offer some mutually beneficial lessons. The unprecedented scale and rapidity of dissemination of recent emerging infectious diseases pose new challenges for vaccine developers, regulators, health authorities and political constituencies. Vaccine manufacturing and distribution are complex and challenging. While speed is essential, clinical development to emergency use authorization and licensure, pharmacovigilance of vaccine safety and surveillance of virus variants are also critical. Access to vaccines and vaccination needs to be prioritized in low- and middle-income countries. The combination of these factors will weigh heavily on the ultimate success of efforts to bring the current and any future emerging infectious disease pandemics to a close. Examination of the vaccine strategies and technical platforms used for the COVID-19 pandemic in the context of those used for previous emerging and reemerging infectious diseases and pandemics can offer critical lessons to prepare for future public health emergencies.

The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to evaluate the safety and characteristics of live, recombinant viral vector vaccines. The Modified Vaccinia Ankara (MVA) vector system is being explored as a platform for development of multiple vaccines. This paper reviews the molecular and biological features specifically of the MVA-BN vector system, followed by a template with details on the safety and characteristics of an MVA-BN based vaccine against Zaire ebolavirus and other filovirus strains. The MVA-BN-Filo vaccine is based on a live, highly attenuated poxviral vector incapable of replicating in human cells and encodes glycoproteins of Ebola virus Zaire, Sudan virus and Marburg virus and the nucleoprotein of the Thai Forest virus. This vaccine has been approved in the European Union in July 2020 as part of a heterologous Ebola vaccination regimen. The MVA-BN vector is attenuated following over 500 serial passages in eggs, showing restricted host tropism and incompetence to replicate in human cells. MVA has six major deletions and other mutations of genes outside these deletions, which all contribute to the replication deficiency in human and other mammalian cells. Attenuation of MVA-BN was demonstrated by safe administration in immunocompromised mice and non-human primates. In multiple clinical trials with the MVA-BN backbone, more than 7800 participants have been vaccinated, demonstrating a safety profile consistent with other licensed, modern vaccines. MVA-BN has been approved as smallpox vaccine in Europe and Canada in 2013, and as smallpox and monkeypox vaccine in the US in 2019. No signal for inflammatory cardiac disorders was identified throughout the MVA-BN development program. This is in sharp contrast to the older, replicating vaccinia smallpox vaccines, which have a known risk for myocarditis and/or pericarditis in up to 1 in 200 vaccinees. MVA-BN-Filo as part of a heterologous Ebola vaccination regimen (Ad26.ZEBOV/MVA-BN-Filo) has undergone clinical testing including Phase III in West Africa and is currently in use in large scale vaccination studies in Central African countries. This paper provides a comprehensive picture of the MVA-BN vector, which has reached regulatory approvals, both as MVA-BN backbone for smallpox/monkeypox, as well as for the MVA-BN-Filo construct as part of an Ebola vaccination regimen, and therefore aims to provide solutions to prevent disease from high-consequence human pathogens.

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.

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.

•A single Ad26.COV2.S booster given 45–75 or 90–240 days after 2 BBIBP-CorV doses was well tolerated.•Robust humoral and cell-mediated immune responses were measured at day 28 in both interval groups.•Humoral responses were strongest against ancestral virus, followed by delta then omicron variants.•T-cell–produced IFN-γ increased ≈10-fold in both groups after this heterologous booster dose. The inactivated COVID-19 whole-virus vaccine BBIBP-CorV has been extensively used worldwide. Heterologous boosting after primary vaccination can induce higher immune responses against SARS-CoV-2 than homologous boosting. The safety and immunogenicity after 28 days of a single Ad26.COV2.S booster dose given at different intervals after 2 doses of BBIBP-CorV are presented. This open-label phase 1/2 trial was conducted in healthy adults in Thailand who had completed 2-dose primary vaccination with BBIBP-CorV. Participants received a single booster dose of Ad26.COV2.S (5 × 1010 virus particles) 90–240 days (Group A1; n = 360) or 45–75 days (Group A2; n = 66) after the second BBIBP-CorV dose. Safety and immunogenicity were assessed over 28 days. Binding IgG antibodies to the full-length pre-fusion Spike and anti-nucleocapsid proteins of SARS-CoV-2 were measured by enzyme-linked immunosorbent assay. The SARS-CoV-2 pseudovirus neutralization assay and live virus microneutralization assay were used to quantify the neutralizing activity of antibodies against ancestral SARS-CoV-2 (Wuhan-Hu-1) and the delta (B.1.617.2) and omicron (B.1.1.529/BA.1 and BA.2) variants. The cell-mediated immune response was measured using a quantitative interferon (IFN)-γ release assay in whole blood. Solicited local and systemic adverse events (AEs) on days 0–7 were mostly mild, as were unsolicited vaccine-related AEs during days 0–28, with no serious AEs. On day 28, anti-Spike binding antibodies increased from baseline by 487- and 146-fold in Groups A1 and A2, and neutralizing antibodies against ancestral SARS-CoV-2 by 55- and 37-fold, respectively. Humoral responses were strongest against ancestral SARS-CoV-2, followed by the delta, then the omicron BA.2 and BA.1 variants. T-cell–produced interferon-γ increased approximately 10-fold in both groups. A single heterologous Ad26.COV2.S booster dose after two BBIBP-CorV doses was well tolerated and induced robust humoral and cell-mediated immune responses measured at day 28 in both interval groups. Clinical Trials Registration. NCT05109559.

•An Ad26.COV2.S booster was given 45–75 or 90–240 days after 2 BBIBP-CorV doses.•Humoral booster responses trended higher after the longer pre-boost interval and against ancestral virus.•Durable T-cell responses were detected in both interval groups.•Hybrid immune responses were higher than booster-effect responses.•Immune responses trended lower but were durable in adults ≥ 60 years. 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. 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). 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. 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.

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.

Inactivated viral vaccines have long been used in humans for diseases of global health threat (e.g., poliomyelitis and pandemic and seasonal influenza) and the technology of inactivation has more recently been used for emerging diseases such as West Nile, Chikungunya, Ross River, SARS and especially for COVID-19. The Brighton Collaboration Benefit-Risk Assessment of VAccines by TechnolOgy (BRAVATO) Working Group has prepared standardized templates to describe the key considerations for the benefit and risk of several vaccine platform technologies, including inactivated viral vaccines. This paper uses the BRAVATO inactivated virus vaccine template to review the features of an inactivated whole chikungunya virus (CHIKV) vaccine that has been evaluated in several preclinical studies and clinical trials. The inactivated whole CHIKV vaccine was cultured on Vero cells and inactivated by ß-propiolactone. This provides an effective, flexible system for high-yield manufacturing. The inactivated whole CHIKV vaccine has favorable thermostability profiles, compatible with vaccine supply chains. Safety data are compiled in the current inactivated whole CHIKV vaccine safety database with unblinded data from the ongoing studies: 850 participants from phase II study (parts A and B) outside of India, and 600 participants from ongoing phase II study in India, and completed phase I clinical studies for 60 subjects. Overall, the inactivated whole CHIKV vaccine has been well tolerated, with no significant safety issues identified. Evaluation of the inactivated whole CHIKV vaccine is continuing, with 1410 participants vaccinated as of 20 April 2022. Extensive evaluation of immunogenicity in humans shows strong, durable humoral immune responses.