Taken together, wobble vaccines represent a novel method for anticipating and preventing viral escape with promising applications in SARS-CoV-2, influenza, HIV, and beyond.
Abstract
Vaccination remains the most successful preventative measure against viral infection, but methods to stably deter rapidly-evolving pathogens have remained elusive. Vaccines capable of incorporating and anticipating viral evolution could address current challenges in seasonal vaccination efforts against SARS-CoV-2 and influenza where economic and disease burdens remain high despite decades of combined study. Rare epitope suppression (RES) is an underutilized concept within vaccine design, where humoral epitope targeting can be molded using complex antigen pools. Based in mRNA vaccine technology, ‘wobble vaccines’ represent the novel application of RES to human pathogens designed to anticipate and resist viral evolution. To establish this platform, public SARS-CoV-2 sequencing data was compiled from the first two years of the COVID-19 pandemic to identify high-diversity sites across the receptor binding domain (RBD) of the spike protein. Wobble RBD (WobbRBD) libraries reflecting that entropy were synthesized and incorporated into established self-amplifying (SA) vaccine constructs. Animals immunized with these complex antigen pools showed no obvious adverse effects. By three days-post vaccination, WobbRBD stimulated robust primary immune activation with distinctive characteristics compared to traditional single-strain vaccine modalities. By day 14, germinal centers, class switching, and antibody-secreting cells were induced, creating potent SARS-CoV-2 spike-binding IgG antibodies. Despite similar overall activation profiles, WobbRBD generated significantly increased breadth against SARS-CoV-2 variant spikes in comparison to single-strain controls – even against future-emerging strains. Taken together, wobble vaccines represent a novel method for anticipating and preventing viral escape with promising applications in SARS-CoV-2, influenza, HIV, and beyond.
Multi pathogen vaccines have emerged as a promising strategy to improve vaccine coverage, simplify immunization logistics, and address overlapping global health threats. However, few vaccine platforms have demonstrated robust and durable immune responses against pathogens spanning distinct biological classes. Here, we developed and evaluated a viral-vectored multipathogen vaccine platform based on a heterologous prime–boost regimen combining the highly attenuated vaccinia virus LC16m8Δ (m8Δ) and adeno-associated virus serotype 1 (AAV1). As a preclinical proof-of-concept, antigen-specific immune responses against
Plasmodium falciparum
and SARS-CoV-2 (Omicron variant) were evaluated, while neutralizing activity against mpox virus was assessed to examine the cross-reactive immunity conferred by the vaccinia virus vector. Immunogenicity, protective efficacy, and transmission-blocking activity were evaluated in murine models and mosquito feeding assays. The heterologous m8Δ prime/AAV1 boost regimen induced robust and long-lasting antigen-specific antibody responses that were maintained for up to 32 weeks. Complete sterile protection against transgenic
Plasmodium berghei
sporozoite challenge was achieved, together with greater than 90% transmission-blocking efficacy in mosquito feeding assays. In parallel, potent neutralizing antibody responses against SARS-CoV-2 Omicron and cross-neutralizing activity against mpox virus were observed. These findings demonstrate the feasibility of the m8Δ/AAV1 platform as a versatile viral-vectored multipathogen vaccine platform capable of integrating protozoan and viral antigens, providing a rationale for further preclinical optimization and clinical evaluation of next generation multipathogen vaccines targeting both endemic and emerging infectious diseases.
Yuna Sato, Yutaro Yamamoto, A. Hasyim et al.· Frontiers in Immunology· 0 citations
This review examines the critical challenge of evolving animal virus resistance to vaccines, a phenomenon threatening veterinary medicine, global food security, and public health. While effective for controlling bacterial diseases, vaccination against rapidly mutating RNA viruses often imposes strong selective pressures, driving the emergence of antigenic variants that evade host immunity. These vaccines escape mutants, evidenced in viruses like canine parvovirus (CPV), avian influenza (AIV), and foot-and-mouth disease (FMD), lead to outbreaks in vaccinated populations and complicate disease management. The paper elucidates the mechanisms behind this resistance, primarily genetic mutations in antigenic sites and sophisticated immune evasion strategies, which enable viruses to circumvent neutralization by vaccine-induced antibodies. It critically evaluates the limitations of current vaccine technologies, including inactivated, live-attenuated, and subunit vaccines, noting that imperfect immunity can inadvertently promote the selection of resistant strains. To address this ongoing evolutionary arms race, the authors advocate for a paradigm shift in vaccine design. They propose leveraging advanced technologies such as viral vector platforms, structural biology, and predictive modeling to develop next-generation vaccines targeting conserved epitopes. Furthermore, the review emphasizes the necessity of global surveillance programs to monitor viral evolution in real-time and calls for a collaborative, interdisciplinary approach to create more robust and future-proof vaccination strategies, thereby mitigating the risk of vaccine-driven viral and ensuring long term efficacy.
Z. Al-Talabani, Anmar Ayoub Al-Obaidi, Shahad Abdul Majeed Aswad· SAR Journal of Pathology and...· 0 citations
ABSTRACT The H9N2 avian influenza virus (AIV) has caused substantial economic losses to the global poultry industry and poses a zoonotic threat to humans. Vaccination constitutes a pivotal strategy for the prevention and control of H9N2 AIVs. However, the ongoing antigenic evolution of the viruses pose a persistent challenge to the protective efficacy of existing vaccines. Therefore, the development of a broadly protective H9N2 influenza vaccine capable of eliciting cross-reactive immune responses is crucial for mitigating both the disease burden and the risk of pandemics. Here, we developed a bivalent chimeric inactivated vaccine, designated cHANA, by combining two individually rescued chimeric inactivated viruses, cHANA1 and cHANA2. Each recombinant virus carries one set of Epigraph-designed HA and NA immunogens, and the two sets were computationally optimized from global H9N2 HA and NA sequence datasets to complement each other in epitope coverage across the H9N2 viral population. Compared to the WHO-recommended candidate vaccine virus (CVV), AL/39, cHANA elicited more potent cross-reactive antibody responses and T cell immunity in mice. Furthermore, it elicited effective cross-protection against lethal challenge with heterologous H9N2 virus and significantly reduced pulmonary viral loads of mice. By conferring broad protective immunity, this vaccine represents a promising universal vaccine candidate for controlling H9N2 outbreaks.
Mengchan Hao, Yiwei Guan, Meng Xu et al.· Emerging Microbes and Infect...· 0 citations
SARS-CoV-2 has evolved into several genetic variants, all bearing mutations that reduce antibody binding and affect vaccine and treatment effectiveness. Updated COVID-19 vaccines, including bivalent formulations (wild type [WT]/BA.1 or WT/BA.5) and more recent monovalent versions targeting emerging variants such as XBB.1.5, JN.1, KP.2 or LP.8.1, were developed to broaden protection. However, immune imprinting may limit the induction of neutralizing antibodies against strains that differ significantly, even after receiving several variant-specific boosters. A deeper understanding of how booster vaccination reshapes antibody specificity remains essential for rational vaccine design. We examined the antibody response to a bivalent WT/BA.5 booster, focusing on antibody levels and neutralization. Serum samples collected before and after a fourth dose of monovalent WT or bivalent (WT/BA.5) mRNA vaccines were compared with sera from individuals after primary WT infections and Omicron BA.1, BA.2, or BA.5 breakthrough infections. We found that both monovalent and bivalent boosters significantly increased IgG and neutralizing antibodies, but breakthrough infections induced broader cross-reactive responses. Depletion experiments revealed that booster-induced immunity was predominantly mediated by cross-reactive antibodies, with the highest levels after breakthrough infections and the lowest after a primary WT infection. These findings provide functional insights into the antibody specificities associated with imprinting effects following variant-adapted booster vaccination.
Iris Medits-Weiss, Dominik Moll, D. Springer et al.· Scientific Reports· 0 citations
The efficacy of viral vector-based vaccines is essential to provide long-term protection and prevention of emerging epidemics and pandemics in parallel to other vaccine platforms. The key challenges of achieving high vaccine efficacy relate to the engineering of highly potent antigens and the generation of long-lasting immunogenicity. Appropriate vaccine development also includes the ability to quickly react to emerging variants and their effects on vaccine efficacy. It can be achieved by booster vaccinations, rapid re-engineering of existing vaccines, but also by targeting conserved regions less prone to mutations, limiting the decrease in efficacy against new variants. Additional aspects involve alternative administration routes, for example, for respiratory infections, the application of intranasal delivery, which can enhance antigenicity and prolong vaccine action. Application of self-amplifying RNA can further potentially improve vaccine efficacy. Vaccine hesitancy has raised concerns about successful coverage of vaccine campaigns. The anti-vaccine campaigns based on misinformation and disinformation have caused serious damage to vaccinations during the Coronavirus disease 2019 (COVID-19) pandemic and to the spread of other infectious diseases.
Kenneth Lundstrom· Exploration of Immunology· 0 citations
