The COVID-19 pandemic, caused by SARS-CoV-2, presents an unprecedented global health crisis. Effective vaccines are crucial for controlling its spread and preventing future outbreaks. While various vaccine types have been developed and deployed, including whole inactivated virus, live-attenuated virus, subunit, viral vector, DNA, and mRNA vaccines, the emergence of new variants necessitates the development of more advanced strategies. This review explores the state-of-the-art in vaccine design, focusing on approaches that address the limitations of existing vaccines and the challenges posed by viral evolution. The three major weapons against infectious diseases are controlling the source of infection, cutting off the transmission route, and protecting susceptible populations, with vaccination being the most cost-effective method for the latter. The rapid development of SARS-CoV-2 vaccines benefited from previous experience with other coronaviruses (SARS-CoV and MERS-CoV) and influenza viruses, accelerating the process. However, the emergence of variants such as Alpha, Beta, Gamma, Delta, and Omicron, with increased transmissibility and immune evasion capabilities, has underscored the need for innovative vaccine design strategies to ensure lasting protection against COVID-19.

The literature review extensively covers various vaccine types developed for COVID-19. It includes studies on the efficacy and safety of mRNA vaccines (BNT162b2 and mRNA-1273), demonstrating high protective efficacy but potential for immune evasion by new variants. Several studies are cited on the limitations of existing vaccines against emerging variants, emphasizing the reduced protective efficacy against some VOCs. The review also surveys research into circular RNA vaccines, chimeric protein-based vaccines, virus vector-based vaccines, and nanoparticle vaccines, exploring their potential as promising candidates to combat COVID-19. Existing studies on structure-guided vaccine design, T-cell-based vaccines, respiratory mucosal delivery, and nanotechnologies are reviewed, providing a foundation for understanding the principles behind these advanced vaccine development strategies.

This is a review article. The authors conducted a comprehensive literature search focusing on publications related to novel SARS-CoV-2 vaccine design strategies. They identified and analyzed studies evaluating various vaccine approaches, including structure-guided design, T-cell-based approaches, mucosal delivery methods, and nanotechnology-enabled platforms. The selection criteria likely included peer-reviewed publications in reputable journals, focusing on preclinical and clinical trial data related to the efficacy, safety, and immunogenicity of the different vaccine candidates. The authors systematically analyzed the advantages and limitations of each approach, comparing their performance characteristics and considering their potential to address the challenge of emerging SARS-CoV-2 variants. This involved integrating information from different research areas, including virology, immunology, structural biology, materials science, and bioinformatics, to provide a holistic overview of advanced vaccine design principles. The final manuscript was drafted through collaborative efforts, involving multiple authors in the writing and critical revision of the text to ensure accuracy and consistency. The authors’ expertise spans several relevant areas contributing to a comprehensive review of the subject matter.

The review highlights four key advanced vaccine design strategies: 1. **Structure-guided vaccine design:** This approach utilizes high-resolution structures of viral proteins (like the spike protein) to design vaccines that stabilize the prefusion conformation, optimizing immunogenicity and neutralizing antibody responses. Examples include S-2P, S-6P (HexaPro), and S-trimer vaccines, which have shown enhanced stability and immunogenicity compared to wild-type spike proteins. The use of RBD dimers, such as ZF2001, is also explored for increased efficacy. 2. **T-cell-based vaccines:** Recognizing the importance of T cell responses in providing long-lasting immunity, this strategy focuses on eliciting strong CD8+ T-cell responses, which are less susceptible to viral mutations. Peptide vaccines and MVA-based vaccines are presented as examples. 3. **Respiratory mucosal delivery:** Intranasal or other mucosal delivery routes aim to induce mucosal IgA and T-cell responses in the respiratory tract, potentially offering more effective protection against infection and transmission. Examples include adenoviral vector vaccines and live-attenuated influenza vaccines, with data suggesting that mucosal delivery can lead to sterilizing immunity in the upper airway, preventing both symptomatic and asymptomatic transmissions. 4. **Nanotechnologies:** Nanoparticle vaccines, including virus-like particles (VLPs), utilize self-assembling nanoparticles to present multiple copies of viral antigens, improving immunogenicity and breadth of protection. Mosaic nanoparticle vaccines that co-display antigens from different variants are shown to elicit cross-reactive immune responses, offering broad protection against diverse SARS-CoV-2 strains. While showing potential, challenges like cost-effectiveness, large-scale manufacturing, and nanotoxicity need further investigation. The review further compares the advantages and limitations of each strategy, highlighting that while structure-guided design improves antigen immunogenicity and yield, it requires high-resolution structures; T-cell-based vaccines provide stronger CD8+ T-cell responses but require identifying specific T-cell epitopes; respiratory mucosal delivery provides rapid mucosal immunity, but with relatively lower serological antibody titers compared to intramuscular injections; and nanotechnologies offer multivalent antigen display but raise concerns about nanotoxicity. The review also discusses the limitations of traditional vaccines in the face of rapidly evolving variants.

The findings of this review directly address the critical need for advanced vaccine design strategies to combat the evolving SARS-CoV-2 pandemic. The various approaches discussed, from structure-guided design enhancing immunogenicity to T-cell-focused vaccines for durable protection, provide a range of potential solutions. The emphasis on mucosal delivery underscores the importance of targeting the initial site of viral entry for effective prevention. Nanoparticle-based vaccines, particularly mosaic designs, show considerable promise in achieving broad protection against multiple variants. However, the challenges associated with these strategies, including cost, scalability, and safety considerations (like nanotoxicity), require further research and development. The review’s findings contribute significantly to the field by synthesizing current knowledge and highlighting crucial areas requiring further investigation, which is pivotal in informing the development of next-generation COVID-19 vaccines and guiding future pandemic preparedness.

This review emphasizes the ongoing need for advanced vaccine design strategies to effectively combat SARS-CoV-2 and its variants. While current vaccines have shown efficacy in reducing severe disease, the emergence of immune-evasive variants necessitates a continuous development of new approaches. Structure-guided design, T-cell focused vaccines, mucosal delivery, and nanotechnologies each present unique advantages, but also face hurdles in terms of feasibility and scalability. Future research should focus on overcoming these challenges, exploring novel adjuvants to enhance immunogenicity, and developing thermostable formulations for wider distribution. Further investigation into the longevity of immune responses and personalized vaccine design approaches is also warranted to ensure long-lasting and universal protection.

As a review article, this study is limited by its reliance on existing published literature. The interpretation of findings is dependent on the quality and comprehensiveness of the included studies. The rapid evolution of SARS-CoV-2 and vaccine development means that new data and technologies may emerge quickly, potentially rendering some aspects of this review outdated. Also, this review doesn't conduct original research or experimental validation of discussed findings.