مقالات پذیرفته شده در نهمین کنگره بین المللی زیست پزشکی
Multivalent Vaccines: Advances, Challenges, and Future Directions in Combating Viral Variants
Multivalent Vaccines: Advances, Challenges, and Future Directions in Combating Viral Variants
Maryam Radmanfard,1,*Asal Naghipour_Kordlar,2
1. Department of Basic Sciences, Ta.C., Islamic Azad University, Tabriz, Iran 2. Faculty of Nursing, Tabriz University of Medical Sciences, Tabriz, Iran
Introduction: Viruses with high antigenic variability (e.g., influenza A, SARS-CoV-2) periodically escape population immunity (Altmann & Boyton, 2022; Saha et al., 2025). Seasonal reformulations and variant-adapted boosters are necessary but reactive (Guest, 2022). Multivalency incorporating antigens from multiple strains/serotypes or pathogens aims to pre-empt escape and simplify schedules (e.g., quadrivalent influenza, pneumococcal conjugates, combination pediatric shots) (Ashraf et al., 2025; Lauer et al., 2016). However, efficacy can be blunted by (i) imprinting preferential recall of memory to prior exposures and (ii) antigenic competition uneven responses when antigens are co-administered (Fatima & Hong, 2025; Zhou et al., 2020). This review condenses platform progress and practical design rules for effective multivalent vaccines.
Methods: Scope & Question: Narrative mini-review addressing: What design/translation principles improve the performance of multivalent vaccines against rapidly evolving respiratory viruses? This focus aligns with recent advances in both COVID-19 and influenza vaccine development (Saha et al., 2025; Ashraf et al., 2025).
Sources & Search: Major databases (PubMed/MEDLINE, Scopus, Web of Science, Google Scholar) were queried for 2020–present English-language literature using combinations of terms: multivalent/polyvalent/bivalent vaccine, antigenic drift/shift, imprinting, antigenic competition, mRNA, adenovirus/MVA, nanoparticle/VLP, adjuvant, universal vaccine (Guest, 2022; Zhou et al., 2020). Reference lists of key reviews and clinical trials were also scanned (Fatima et al., 2024).
Selection & Synthesis: Priority was given to peer-reviewed platform studies, clinical trials, and high-quality real-world effectiveness analyses for COVID-19 and influenza (Altmann & Boyton, 2022; Halfmann et al., 2025), plus exemplars from licensed multiserotype vaccines such as pneumococcal and meningococcal conjugates (Lauer et al., 2016). Data were qualitatively synthesized into themes: platform capabilities, immunological constraints, translational/logistical considerations, and actionable design strategies. No meta-analysis was attempted.
Results: mRNA (LNP-delivered): Fast, modular encoding of multiple antigens; straightforward variant updates; challenges include cold-chain, reactogenicity, and optimizing multicomponent expression balance within shared LNPs (Fatima et al., 2024; Saha et al., 2025).
• Viral vectors (Ad26/ChAdOx1, MVA, VSV): Strong cellular immunity; pre-existing anti-vector immunity addressed by rare/nonhuman serotypes and heterologous prime-boost with non-vector platforms (Guest, 2022; Miryala & Swain, 2025).
• Protein/VLP/nanoparticle: Excellent safety/thermostability; adjuvant-dependent potency; programmable co-display of heterologous antigens (e.g., mosaic RBDs, ferritin scaffolds) to shape breadth and dampen immunodominance (Zhou et al., 2020; Ashraf et al., 2025).
• Variant-updated/bivalent COVID-19 vaccines show improved neutralization against targeted variants and clinically meaningful protection versus severe outcomes relative to no recent vaccination (Altmann & Boyton, 2022; Halfmann et al., 2025).
• Quadrivalent influenza vaccines remain the archetype of multivalency; cell-based manufacturing can modestly improve effectiveness versus egg-based due to fewer egg-adaptation changes (Ashraf et al., 2025; Fatima & Hong, 2025).
• Combination programs (e.g., influenza + COVID-19 ± RSV) demonstrate feasibility but highlight formulation trade-offs (e.g., balancing responses to influenza B alongside SARS-CoV-2) (Fatima & Hong, 2025; Saha et al., 2025).
• Imprinting (OAS): Strong boosting of ancestral memory can suppress de novo responses. Mitigations: select components with sufficient antigenic distance to recruit naïve B cells; prioritize conserved epitopes (HA stem, S2/stem-like regions); adjust dose/adjuvant to favor germinal center renewal (Altmann & Boyton, 2022; Halfmann et al., 2025).
• Antigenic competition: Co-formulated antigens can yield skewed responses. Mitigations: titrate antigen ratios, use potent, mechanism-aligned adjuvants (e.g., saponin/MPLA systems), and co-display antigens on the same nanoparticle to ensure co-delivery to the same APCs and harmonize T-cell help (Zhou et al., 2020; Fatima & Hong, 2025).
• Manufacturing: Chemistry-Manufacturing-Controls (CMC) complexity scales with valency; standardized assays for each component (identity, potency) and for the final blend are essential (Guest, 2022; Lauer et al., 2016).
• Logistics: Thermostability is pivotal for equitable access; protein/VLP options offer an advantage today; lyophilized or next-gen LNPs are active areas of development (Ashraf et al., 2025; Fatima et al., 2024).
• Evaluation: Immuno-bridging to licensed comparators accelerates updates, but requires robust pharmacovigilance and effectiveness monitoring across age/risk strata (Saha et al., 2025; Guest, 2022).
Discussion (concise design framework)
1. Choose the right targets: Combining conserved regions for durability with antigenically distanced variant antigens is essential to overcome imprinting and broaden protective immunity (Halfmann et al., 2025; Altmann & Boyton, 2022).
2. Engineer presentation: Structured co-display systems such as mosaic or spiked nanoparticles are preferable to simple antigen cocktails because they reduce immunodominance and harmonize immune responses (Zhou et al., 2020; Ashraf et al., 2025).
3. Tune formulation: Optimizing per-component dose and adjuvant selection helps flatten immunodominance hierarchies; heterologous prime-boost schedules may also bypass anti-vector immunity (Guest, 2022; Miryala & Swain, 2025).
4. Design for delivery: Thermostability and scalable production should be incorporated early, with attention to platform-agnostic fill-finish processes and modular CMC considerations (Fatima et al., 2024; Ashraf et al., 2025).
5. Measure what matters: Evaluation should employ harmonized breadth indices (cross-neutralization panels), T-cell polyfunctionality, and correlates of protection alongside traditional antibody titers to ensure meaningful clinical insights (Saha et al., 2025; Fatima & Hong, 2025).
Conclusion: Multivalent vaccination is essential for keeping pace with antigenically dynamic viruses, but success depends on more than simply adding antigens (Altmann & Boyton, 2022; Saha et al., 2025). Effective designs require integration of rational antigen selection and controlled antigenic distance, alongside nanoparticle co-display and optimized formulation strategies to curb competition (Zhou et al., 2020; Ashraf et al., 2025). Additionally, manufacturability and thermostability must be prioritized to ensure equitable global deployment (Fatima et al., 2024; Lauer et al., 2016). With standardized evaluation methods and vigilant real-world monitoring, multivalent and ultimately broadly protective vaccines can transition from reactive measures to proactive, durable solutions for population immunity (Guest, 2022; Halfmann et al., 2025).