Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged at the end of 2019 and is responsible for the largest human pandemic in 100 years. Thirty-four vaccines are currently approved for use worldwide, and approximately 67% of the world population has received a complete primary series of one, yet countries are dealing with new waves of infections, variant viruses continue to emerge, and breakthrough infections are frequent secondary to waning immunity. Here, we evaluate a measles virus (MV)-vectored vaccine expressing a stabilized prefusion SARS-CoV-2 spike (S) protein (MV-ATU3-S2PΔF2A; V591) with demonstrated immunogenicity in mouse models (see companion article [J. Brunet, Z. Choucha, M. Gransagne, H. Tabbal, M.-W. Ku et al., J Virol 98:e01693-23, 2024, https://doi.org/10.1128/jvi.01693-23]) in an established African green monkey model of disease. Animals were vaccinated with V591 or the control vaccine (an equivalent MV-vectored vaccine with an irrelevant antigen) intramuscularly using a prime/boost schedule, followed by challenge with an early pandemic isolate of SARS-CoV-2 at 56 days post-vaccination. Pre-challenge, only V591-vaccinated animals developed S-specific antibodies that had virus-neutralizing activity as well as S-specific T cells. Following the challenge, V591-vaccinated animals had lower infectious virus and viral (v) RNA loads in mucosal secretions and stopped shedding virus in these secretions earlier. vRNA loads were lower in these animals in respiratory and gastrointestinal tract tissues at necropsy. This correlated with a lower disease burden in the lungs as quantified by PET/CT at early and late time points post-challenge and by pathological analysis at necropsy.IMPORTANCESevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the largest human pandemic in 100 years. Even though vaccines are currently available, countries are dealing with new waves of infections, variant viruses continue to emerge, breakthrough infections are frequent, and vaccine hesitancy persists. This study uses a safe and effective measles vaccine as a platform for vaccination against SARS-CoV-2. The candidate vaccine was used to vaccinate African green monkeys (AGMs). All vaccinated AGMs developed robust antigen-specific immune responses. After challenge, these AGMs produced less virus in mucosal secretions, for a shorter period, and had a reduced disease burden in the lungs compared to control animals. At necropsy, lower levels of viral RNA were detected in tissue samples from vaccinated animals, and the lungs of these animals lacked the histologic hallmarks of SARS-CoV-2 disease observed exclusively in the control AGMs.

Newcastle disease virus (NDV) is an avian virus and a promising vector for the development of vaccines for veterinary and human use. The optimal vaccine vector performance requires a stable high-level expression of a transgene. The foreign genes are usually incorporated in the genome of NDV as individual transcription units, whose transcription and subsequent translation of the mRNA are regulated by the 5\' and 3\' untranslated regions (UTRs) flanking the open reading frame of the transgene. Here, we investigated if the UTRs derived from the cognate NDV genes would increase the expression of a model protective antigene from an NDV vector. Our results show that in chicken DF1 cells, none of the UTRs tested significantly outperformed generic short sequences flanking the transgene, while in human HeLa cells, UTRs derived from the M gene of NDV statistically significantly increased the expression of the transgene. The UTRs derived from the HN gene significantly downregulated the transgene expression in both cell cultures. Further experiments demonstrated that NDV UTRs differently affect the mRNA abundance and translation efficacy. While both M and HN UTRs decreased the level of the transgene mRNA in infected cells compared to the mRNA flanked by generic UTRs, M, and particularly, HN UTRs strongly increased the mRNA translation efficacy. The major determinants of translation enhancement are localized in the 5\'UTR of HN. Thus, our data reveal a direct role of NDV UTRs in translational regulation, and inform future optimization of NDV vectors for vaccine and therapeutic use.

The present study aimed to estimate the reporting rates (RRs) of acute kidney injury (AKI) and renal failure (RF) after COVID-19 vaccination in the European Economic Area (EEA) and the United States.
We retrieved and analyzed pharmacovigilance data on suspected AKI and RF cases and fatalities post COVID-19 vaccination with licensed vaccines reported to EudraVigilance and VAERS between week 52/2020 and week 52/2022 or week 1/2023, respectively. Reporting rates with 95% confidence intervals were estimated per million administered vaccine doses.
In total, 4,244 AKI and 1,557 RF suspected cases were notified to EudraVigilance (1,692 AKI/971 RF) and VAERS (2,552 AKI/586 RF) during the study period following the administration of >1.6 billion COVID-19 vaccine doses (EEA: 970,934,453/US: 666,511,603). The overall RRs were 3.03 (95 % CI: 2.94-3.12) for AKI and 1.11 (95 % CI: 1.06-1.17) for RF per million administered vaccine doses. Indices for statistically significant increased risks were found in subjects, especially males, ≥65 years compared to 18-64 years old (AKI: OR = 7.23, 95 % CI: 6.63-7.88, p = 0.000, and RF: OR = 4.74, 95 % CI: 3.99-5.63, p < 0.001). AKI reporting rates were higher in the US, while RF reporting rates were higher in Europe. Both potential side effects were elevated following vectored rather than mRNA vaccines, with the highest reporting rates post AD26.COV2.S vaccination in the US (AKI: RR = 12.24, 95 % CI: 10.66-13.81; RF: RR = 3.17, 95 % CI: 2.36-3.97). There were 1,312 deaths possibly associated with AKI (RR = 0.94, 95 % CI: 0.89-0.99) and 460 deaths possibly associated with RF (RR = 0.33, 95 % CI: 0.30-0.36) per million vaccine doses. Fatalities were lower in Europe than in the US (AKI: OR = 0.25, 95 % CI: 0.22-0.28, p < 0.001; RF: OR = 0.82, 95 % CI: 0.69-0.99, p = 0.036).
AKI and RF may be observed rarely following vaccination against COVID-19. Further studies are warranted to confirm these findings and uncover the underlying pathophysiological mechanism.

Influenza A viruses (IAV-S) belonging to the H1 subtype are endemic in swine worldwide. Antigenic drift and antigenic shift lead to a substantial antigenic diversity in circulating IAV-S strains. As a result, the most commonly used vaccines based on whole inactivated viruses (WIVs) provide low protection against divergent H1 strains due to the mismatch between the vaccine virus strain and the circulating one. Here, a consensus coding sequence of the full-length of HA from H1 subtype was generated in silico after alignment of the sequences from IAV-S isolates obtained from public databases and was delivered to pigs using the Orf virus (ORFV) vector platform. The immunogenicity and protective efficacy of the resulting ORFVΔ121conH1 recombinant virus were evaluated against divergent IAV-S strains in piglets. Virus shedding after intranasal/intratracheal challenge with two IAV-S strains was assessed by real-time RT-PCR and virus titration. Viral genome copies and infectious virus load were reduced in nasal secretions of immunized animals. Flow cytometry analysis showed that the frequency of T helper/memory cells, as well as cytotoxic T lymphocytes (CTLs), were significantly higher in the peripheral blood mononuclear cells (PBMCs) of the vaccinated groups compared to unvaccinated animals when they were challenged with a pandemic strain of IAV H1N1 (CA/09). Interestingly, the percentage of T cells was higher in the bronchoalveolar lavage of vaccinated animals in relation to unvaccinated animals in the groups challenged with a H1N1 from the gamma clade (OH/07). In summary, delivery of the consensus HA from the H1 IAV-S subtype by the parapoxvirus ORFV vector decreased shedding of infectious virus and viral load of IAV-S in nasal secretions and induced cellular protective immunity against divergent influenza viruses in swine.

Virus-like particles (VLPs), composed of the small hepatitis B virus surface antigen (HBsAgS), are the antigenic components of the hepatitis B virus (HBV) vaccine and represent the backbones for a chimeric anti-malaria vaccine and various vaccine candidates. Biological vectors have to face pre-existing anti-vector immune responses due to previous immune exposure. Vector recognition after natural infections or vaccinations can result in unwarranted outcomes, with compromising effects on clinical outcomes. In order to evaluate the impact of a pre-existing anti-HBsAgS immune response, we developed mutant VLPs composed of subunits with reduced HBsAgS-specific antigenicity. The insertion of a Plasmodium falciparum circumsporozoite protein (CSP)-derived epitope as a read-out allowed the assessment of wild type (wt) and mutant VLPs in the context of a pre-existing immune response. Mutant and wt VLP platforms with a CSP-epitope insert are immunogenic and have the ability to generate anti-CSP antibody responses in both naïve BALB/c mice and mice with a pre-existing anti-HBsAgS immune response, but with superior anti-CSP responses in mice with a pre-existing immunity. The data indicate that previous HBsAgS exposure facilitates enhanced antibody responses against foreign epitopes delivered by the HBsAgS platform, and, in this context, the state of immune sensitization alters the outcome of subsequent vaccinations.

Introduction: Human respiratory syncytial virus (RSV) is a major health threat both for the very young and the elderly. With yearly 3.2 million hospital admissions and approximately 118,000 deaths due to RSV in children across the globe, the impact of this infectious disease is very high. Development of a safe RSV vaccine is of utmost importance but has proven to be challenging for several reasons. Researchers are faced with the history of a failed RSV vaccine trial, difficult target populations, a virus that naturally does not induce a long-lasting immune response and ambiguity concerning the optimal correlate of protection. Many different vaccine formats are being tested in preclinical models and about 30 candidate RSV vaccines are being evaluated in clinical trials.Areas covered: In this review we focus on the difficulties concerning the development of an effective RSV vaccine and discuss vaccines that are currently in clinical trials and how they have dealt with these challenges. We review live-attenuated vaccines, vectored vaccines, subunit vaccines and particle-based vaccines.Expert opinion: It is clear that this field is progressing rapidly with several promising RSV vaccine candidates. A safe and effective RSV vaccine might be on the brink of clinical implementation soon.

The development of a cytomegalovirus (CMV) vaccine has become a top priority due to its potential cost-effectiveness and associated public health benefits. However, there are a number of challenges facing vaccine development including the following: (1) CMV has many mechanisms for evading immune responses , and natural immunity is not perfect, (2) the immune correlates for protection are unclear, (3) a narrow range of CMV hosts limits the value of animal models, and (4) the placenta is a specialized organ formed transiently and its immunological status changes with time. In spite of these limitations, several types of CMV vaccine candidate, including live-attenuated, DISC , subunit, DNA, vectored, and peptide vaccines, have been developed or are currently under development. The recognition of the pentameric complex as the major neutralization target and identification of various strategies to block viral immune response evasion mechanisms have opened new avenues to CMV vaccine development. Here, we discuss the immune correlates for protection, the characteristics of the various vaccine candidates and their clinical trials, and the relevant animal models.

Efforts to make vaccines against infectious diseases and immunotherapies for cancer have evolved to utilize a variety of heterologous expression systems such as viral vectors. These vectors are often attenuated or engineered to safely deliver genes encoding antigens of different pathogens. Adenovirus and poxvirus vectors are among the viral vectors that are most frequently used to develop prophylactic vaccines against infectious diseases as well as therapeutic cancer vaccines. This mini-review describes the trends and processes in large-scale production of adenovirus and poxvirus vectors to meet the needs of clinical applications. We briefly describe the general principles for the production and purification of adenovirus and poxvirus viral vectors. Currently, adenovirus and poxvirus vector manufacturing methods rely on well-established cell culture technologies. Several improvements have been evaluated to increase the yield and to reduce the overall manufacturing cost, such as cultivation at high cell densities and continuous downstream processing. Additionally, advancements in vector characterization will greatly facilitate the development of novel vectored vaccine candidates.

Live attenuated vaccines against human viral diseases have been amongst the most successful cost effective interventions in medical history. Smallpox was declared eradicated in 1980; poliomyelitis is nearing global eradication and measles has been controlled in most parts of the world. Vaccines function well for acute diseases such as these but chronic infections such as HIV are more challenging for reasons of both likely safety and probable efficacy. The derivation of the vaccines used has in general not been purely rational except in the sense that it has involved careful clinical trials of candidates and subsequent careful follow up in clinical use; the identification of the candidates is reviewed.