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A resurgence of yellow fever disease in multiple African countries has proved difficult to control. Given that we have a highly effective vaccine that confers lifelong immunity, why is yellow fever still a problem? Much of the answer lies in vaccine supply and demand. Yellow fever, caused by yellow fever virus, is a mosquito-borne flavivirus disease; it is found in sub-Saharan Africa and tropical South America, where approximately 1 billion people in 46 countries are at risk for it. A live attenuated vaccine (strain 17D) was developed by Max Theiler and colleagues in the 1930s — work that earned Theiler a Nobel Prize. An excellent vaccine, it has been in use since 1937; more than 650 million doses have been distributed in the past 75 years, and 1 dose probably confers lifelong protective immunity. The disease, however, has not been conquered: there are still . . .

Yellow fever (YF) is regarded as the original hemorrhagic fever and has been a major public health problem for at least 250years. A very effective live attenuated vaccine, strain 17D, was developed in the 1930s and this has proved critical in the control of the disease. There is little doubt that without the vaccine, YF virus would be considered a biosafety level 4 pathogen. Significantly, YF is currently the only disease where an international vaccination certificate is required under the International Health Regulations. Despite having a very successful vaccine, there are occasional issues of supply and demand, such as that which occurred in Angola and Democratic Republic of Congo in 2016 when there was insufficient vaccine available. For the first time fractional dosing of the vaccine was approved on an emergency basis. Thus, continued vigilance and improvements in supply and demand are needed in the future.

•We investigated monovalent and tetravalent formulations of TDV in AG129 mice.•They were immunogenic and elicited neutralizing Ab and cellular responses.•Both formulations protected mice against a newly mouse adapted DENV-4 strain. Dengue (DEN) is the most important mosquito-borne viral disease, with a major impact on global health and economics, caused by four serologically and distinct viruses termed DENV-1 to DENV-4. Currently, there is no licensed vaccine to prevent DEN. We have developed a live attenuated tetravalent DENV vaccine candidate (TDV) (formally known as DENVax) that has shown promise in preclinical and clinical studies and elicits neutralizing antibody responses to all four DENVs. As these responses are lowest to DENV-4 we have used the AG129 mouse model to investigate the immunogenicity of monovalent TDV-4 or tetravalent TDV vaccines, and their efficacy against lethal DENV-4 challenge. Since the common backbone of TDV is based on an attenuated DENV-2 strain (TDV-2) we also tested the efficacy of TDV-2 against DENV-4 challenge. Single doses of the tetravalent or monovalent vaccines elicited neutralizing antibodies, anti-NS1 antibodies, and cellular responses to both envelope and nonstructural proteins. All vaccinated animals were protected against challenge at 60 days post-immunization, whereas all control animals died. Investigation of DENV-4 viremias post-challenge showed that only the control animals had high viremias on day 3 post-challenge, whereas vaccinated mice had no detectable viremia. Overall, these data highlight the excellent immunogenicity and efficacy profile of our candidate dengue vaccine in AG129 mice.

► NS1N130A commonly reverted for the NS1130A/175A/207A virus in mice. ► Asparagine to serine/glutamine further attenuated the virus at the NS1130 site. ► Only NS1130-132QQA/175A/207A was highly attenuated in weanling and adult mice. ► Attenuated mutant viruses induced a protective immune response following lethal challenge. West Nile virus (WNV), like all members of the Japanese encephalitis (JE) serogroup except JE virus, contains three N-linked glycosylation (N-X-S/T) sites in the NS1 protein at asparagine residues NS1130, NS1175 and NS1207. Previously we showed that the ablation of these glycosylation sites in WNV, by substitution of asparagine for alanine, attenuated mouse neuroinvasiveness; however, full attenuation was not achieved and the virus retained a neurovirulence phenotype. Sequence of viral RNA extracted from mouse brains revealed a reversion at the NS1130 site in some mice that succumbed to the attenuated NS1130A/175A/207A strain. Here, we further attenuated WNV by mutating the asparagine to serine or glutamine in addition to mutating other residues in the NS1130-132 glycosylation motif. These mutants proved to further attenuate WNV for both neuroinvasiveness and neurovirulence in mice. NS1130-132QQA/175A/207A, the most attenuated mutant virus, showed modest changes in infectivity titers versus the parental strain, was not temperature sensitive, and did not show reversion in mice. Mutant virus was completely attenuated for neuroinvasiveness after intraperitoneal inoculation with >1,000,000 PFU, and mice were protected against lethal challenge. Overall, we showed that changing the asparagine of the NS1130 glycosylation motif to a serine or glutamine attenuated WNV further than the asparagine to alanine substitution. Further, mutating all three of the amino acids of the NS1130-132 glycosylation motif (NTT-QQA) along with NS1175 and NS1207 asparagine to alanine mutations gave the most stable and attenuated strain.

Although West Nile virus (WNV) has been a prominent mosquito-transmitted infection in North America for twenty years, no human vaccine has been licensed. With a cumulative number of 24,714 neurological disease cases and 2314 deaths in the U.S. since 1999, plus a large outbreak in Europe in 2018 involving over 2000 human cases in 15 countries, a vaccine is essential to prevent continued morbidity, mortality, and economic burden. Currently, four veterinary vaccines are licensed, and six vaccines have progressed into clinical trials in humans. All four veterinary vaccines require multiple primary doses and annual boosters, but for a human vaccine to be protective and cost effective in the most vulnerable older age population, it is ideal that the vaccine be strongly immunogenic with only a single dose and without subsequent annual boosters. Of six human vaccine candidates, the two live, attenuated vaccines were the only ones that elicited strong immunity after a single dose. As none of these candidates have yet progressed beyond phase II clinical trials, development of new candidate vaccines and improvement of vaccination strategies remains an important area of research.

Yellow Fever (YF), a mosquito-borne viral disease caused by yellow fever virus (YFV), remains endemic in tropical Sub-Saharan Africa and South America. The 17D live-attenuated vaccine has significantly reduced YF incidence with minimal risk of vaccine-associated adverse events, including Yellow Fever Vaccine–fever-associated Neurotropic Disease (YEL-AND) and Yellow Fever Vaccine–Associated Viscerotropic Disease (YEL-AVD). This study investigates the potential of Real-World Evidence (RWE) to enhance vaccine surveillance by analyzing electronic health records (EHRs) from the TriNetX platform, which identified a total of 15,835 individuals who were vaccinated with the Stamaril® YF vaccine between 2017 and 2021 in the United States. We compared adverse event rates obtained from RWE with those reported by the manufacturer in a recent study of Stamaril® used in the United States during this period. Our findings were consistent with those published previously and suggest no significant increase in adverse medical outcomes post-vaccination across all age groups, particularly in long-term analysis. This proof-of-concept study underscores the value of RWE in monitoring vaccine safety and supports its potential to complement traditional surveillance methods, offering a robust tool for continuous post-marketing vaccine evaluation. •Real-world evidence (RWE) was able to identify 15,835 individuals from the Sanofi study.•RWE had similar results to Sanofi surveillance, supporting the utility of RWE in studying immunization.•No statistically significant long-term adverse events were identified following yellow fever vaccination.

Chikungunya virus (CHIKV) a mosquito-borne alphavirus is the causative agent of Chikungunya (CHIK), a disease with low mortality but high acute and chronic morbidity resulting in a high overall burden of disease. After the acute disease phase, chronic disease including persistent arthralgia is very common, and can cause fatigue and pain that is severe enough to limit normal activities. On average, around 40% of people infected with CHIKV will develop chronic arthritis, which may last for months or years. Recommendations for protection from CHIKV focus on infection control through preventing mosquito proliferation. There is currently no licensed antiviral drug or vaccine against CHIKV. Therefore, one of the most important public health impacts of vaccination would be to decrease burden of disease and economic losses in areas impacted by the virus, and prevent or reduce chronic morbidity associated with CHIK. This benefit would particularly be seen in Low and Middle Income Countries (LMIC) and socio-economically deprived areas, as they are more likely to have more infections and more severe outcomes. This ‘Vaccine Value Profile’ (VVP) for CHIK is intended to provide a high-level, holistic assessment of the information and data that are currently available to inform the potential public health, economic and societal value of vaccines in the development pipeline and vaccine-like products.This VVP was developed by a working group of subject matter experts from academia, non-profit organizations, public private partnerships, and multi-lateral organizations. All contributors have extensive expertise on various elements of the CHIK VVP and collectively aimed to identify current research and knowledge gaps.The VVP was developed using only existing and publicly available information.

•Without immune correlates, dengue vaccine efficacy trials require clinical endpoints.•Recent evidence impacts trial design and follow-up of 2nd generation dengue vaccines.•Vaccine safety and efficacy stratified by pre-vaccination serostatus is essential.•Trial data should be interpreted with consideration of transient heterotypic immunity. Licensing and decisions on public health use of a vaccine rely on a robust clinical development program that permits a risk-benefit assessment of the product in the target population. Studies undertaken early in clinical development, as well as well-designed pivotal trials, allow for this robust characterization. In 2012, WHO published guidelines on the quality, safety and efficacy of live attenuated dengue tetravalent vaccines. Subsequently, efficacy and longer-term follow-up data have become available from two Phase 3 trials of a dengue vaccine, conducted in parallel, and the vaccine was licensed in December 2015. The findings and interpretation of the results from these trials released both before and after licensure have highlighted key complexities for tetravalent dengue vaccines, including concerns vaccination could increase the incidence of dengue disease in certain subpopulations. This report summarizes clinical and regulatory points for consideration that may guide vaccine developers on some aspects of trial design and facilitate regulatory review to enable broader public health recommendations for second-generation dengue vaccines.

Dengue is a mosquito-borne disease caused by four serologically and genetically related viruses termed DENV-1 to DENV-4. With an annual global burden of approximately 390 million infections occurring in the tropics and subtropics worldwide, an effective vaccine to combat dengue is urgently needed. Historically, a major impediment to dengue research has been development of a suitable small animal infection model that mimics the features of human illness in the absence of neurologic disease that was the hallmark of earlier mouse models. Recent advances in immunocompromised murine infection models have resulted in development of lethal DENV-2, DENV-3 and DENV-4 models in AG129 mice that are deficient in both the interferon-α/β receptor (IFN-α/β R) and the interferon-γ receptor (IFN-γR). These models mimic many hallmark features of dengue disease in humans, such as viremia, thrombocytopenia, vascular leakage, and cytokine storm. Importantly AG129 mice develop lethal, acute, disseminated infection with systemic viral loads, which is characteristic of typical dengue illness. Infected AG129 mice generate an antibody response to DENV, and antibody-dependent enhancement (ADE) models have been established by both passive and maternal transfer of DENV-immune sera. Several steps have been taken to refine DENV mouse models. Viruses generated by peripheral in vivo passages incur substitutions that provide a virulent phenotype using smaller inocula. Because IFN signaling has a major role in immunity to DENV, mice that generate a cellular immune response are desired, but striking the balance between susceptibility to DENV and intact immunity is complicated. Great strides have been made using single-deficient IFN-α/βR mice for DENV-2 infection, and conditional knockdowns may offer additional approaches to provide a panoramic view that includes viral virulence and host immunity. Ultimately, the DENV AG129 mouse models result in reproducible lethality and offer multiple disease parameters to evaluate protection by candidate vaccines.

The ongoing Zika epidemic and its consequences demand rapid development of a safe, efficacious vaccine. As preclinical studies of vaccine candidates continue in parallel with human trials, we need to determine which questions will inform short-term development plans. Studies have demonstrated that various Zika virus (ZIKV) vaccine constructs generate protective immune responses in mice and nonhuman primates, 1 , 2 and two DNA ZIKV vaccine candidates have entered phase 1 human safety testing (ClinicalTrials.gov numbers, NCT01099852 and NCT02840487). ZIKV vaccine development is advancing rapidly thanks to collaborations among academia, governments, and industry. Current knowledge gaps related to the properties, epidemiology, and pathology of ZIKV increase the complexity of vaccine development (see Table 1), but historical success in developing other flavivirus vaccines encourages optimism. An ongoing epidemic in the Americas and the impact of ZIKV congenital syndrome (ZCS) necessitate rapid development of a . . .