The COVID-19 pandemic accelerated the rapid development and distribution of various vaccine platforms, resulting in a significant reduction in disease severity, hospitalizations, and mortality. However, persistent challenges remain concerning the durability and breadth of vaccine-induced protection, especially in the face of emerging SARS-CoV-2 variants. This review aimed to evaluate the factors influencing the immunogenicity and effectiveness of COVID-19 vaccines to inform future vaccine advancement strategies. A narrative review with systematic approach was conducted following PRISMA guidelines for narrative review. Literature was sourced from databases including PubMed, Embase, and Web of Science for studies published between December 2019 and May 2025. Encompassed studies assessed vaccine efficacy, immunogenicity, and safety across various populations and vaccine platforms. Data were collected qualitatively, with quantitative data from reviews highlighted where available. We have uncovered a decline in vaccine efficacy over time and weakened protection against novel variants such as Delta and Omicron. Booster doses, specifically heterologous regimens, improved immunogenicity and increased protection. Vaccine-induced neutralizing antibody titers have been found to correlate with clinical protection, although the long-term correlates of immunity remain poorly defined. The induction of IgG4 antibodies after repeated mRNA vaccinations raised concerns about potential modulation of the immune response. COVID-19 vaccines have contributed significantly to pandemic control; however, their efficacy is limited by the evolution of the virus and declining immunity. Forthcoming vaccine strategies should focus on broad-spectrum, variant-adapted formulations and defining robust comparisons of protection. Recognizing the immunological basis of vaccine response, including the role of specific antibody subclasses, is fundamental for optimizing long-term protection.

COVID-19, being a life-threatening infection that evolves rapidly, remains a major public health concern calling for the development of vaccines with broad protection against different pathogenic strains and high immunogenicity. Aside from this, other concerns in mass immunization settings are also the scalability of production and relative affordability of the technology. In that regard, adjuvanted protein vaccines with particles mimicking the virus stand out among known vaccine technologies. The “Betuvax-CoV-2” vaccine, developed on the basis of a recombinant protein and an adjuvant, has already been tested in preclinical studies and has advanced to clinical evaluation. Open, double-blinded, placebo-controlled, randomized phase I/II clinical trial of the “Betuvax-CoV-2,” recombinant protein subunit vaccine based on the S-protein RBD fused with the Fc-fragment of IgG, was conducted to evaluate safety and immunogenicity in response to the vaccination. Methods: In the phase I/II clinical trial, 116 healthy adult men and women, ages 18–58, were enrolled: 20 in Stage I, and 96 in Stage II. In Stage I, 20 µg of the vaccine was administered intramuscularly on day 2, and either 5 µg (group 1) or 20 µg (group 2) on day 30. In Stage II, 20 µg of the vaccine was administered intramuscularly on day 2, and either 5 µg (group 3) or 20 µg (group 4) on day 30. In group 5, both injections were replaced with placebo. The primary outcome measures were safety (number of participants with adverse events throughout the study) and antigen-specific humoral immunity (SARS-CoV-2-specific antibodies measured by ELISA and CMIA). Antigen-specific cell-mediated immunity and changes in neutralizing antibodies (detected with a SARS-CoV-2 neutralization assay) were measured as a secondary outcome. The trial is registered with ClinicalTrials.gov (Study Identifier: NCT05270954). Findings: Both vaccine formulations (20 µg + 5 µg and 20 µg + 20 µg) were safe and well tolerated. Most adverse events were mild, and no serious adverse events were detected. On day 51,anti-SARS-CoV-2 total and IgG antibody titers and anti-SARS-CoV-2 neutralizing antibodies were significantly higher in the vaccine groups (both formulations) than in the placebo. A more pronounced CD4+-mediated immune response was observed in the group of volunteers administered with the 20 + 20 μg vaccine formulation. Interpretations: RBD-Fc-based COVID-19 “Betuvax-CoV-2” vaccine in doses (20 + 5 µg and 20 + 20 µg) demonstrated an excellent safety profile and induced a strong humoral response. Further research on the protective effectiveness of the “Betuvax-CoV-2” vaccine for the prevention of COVID-19 is on its way.

Public health threat coming from a rapidly developing COVID-19 pandemic calls for developing safe and effective vaccines with innovative designs. This paper presents preclinical trial results of “Betuvax-CoV-2”, a vaccine developed as a subunit vaccine containing a recombinant RBD-Fc fusion protein and betulin-based spherical virus-like nanoparticles as an adjuvant (“Betuspheres”). The study aimed to demonstrate vaccine safety in mice, rats, and Chinchilla rabbits through acute, subchronic, and reproductive toxicity studies. Along with safety, the vaccine demonstrated protective efficacy through SARS-CoV-2-neutralizing antibody production in mice, rats, hamsters, rabbits, and primates (rhesus macaque), and lung damage and infection protection in hamsters and rhesus macaque model. Eventually, “Betuvax-CoV-2” was proved to confer superior efficacy and protection against the SARS-CoV-2 in preclinical studies. Based on the above results, the vaccine was enabled to enter clinical trials that are currently underway.

Public health threat coming from a rapidly developing COVID-19 pandemic calls for developing safe and effective vaccines with innovative designs. This paper presents preclinical trial results of “Betuvax-CoV-2”, a vaccine developed as a subunit vaccine containing a recombinant RBD-Fc fusion protein and betulin-based spherical virus-like nanoparticles as an adjuvant (“Betuspheres”). The aim of the study was to demonstrate vaccine safety in mice, rats, and Chinchilla rabbits through acute, subchronic, and reproductive toxicity studies. Along with safety, the vaccine demonstrated protective efficacy through SARS-CoV-2-neutralizing antibody production in mice, rats, hamsters, rabbits, and primates (rhesus macaque), and lung damage and infection protection in hamsters and rhesus macaque model. Eventually, “Betuvax-CoV-2” was proved to confer superior efficacy and protection against the SARS-CoV-2 in preclinical studies. Based on the above results, the vaccine was enabled to enter clinical trials that are currently underway.