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The Development of Epitope-Based Recombinant Protein Vaccines against SARS-CoV-2

Khalid K, Lim HX, Hwang JS, Poh CL

AAPS J, 2024 Aug 13;26(5):93.
PMID: 39138686 DOI: 10.1208/s12248-024-00963-1

The COVID-19 pandemic continues to cause infections and deaths, which are attributable to the SARS-CoV-2 Omicron variant of concern (VOC). Moderna's response to the declining protective efficacies of current SARS-CoV-2 vaccines against Omicron was to develop a bivalent booster vaccine based on the Spike (S) protein from the Wuhan and Omicron BA.4/BA.5 strains. This approach, while commendable, is unfeasible in light of rapidly emerging mutated viral strains. PubMed and Google Scholar were systematically reviewed for peer-reviewed papers up to January 2024. Articles included focused on specific themes such as the clinical history of recombinant protein vaccine development against different diseases, including COVID-19, the production of recombinant protein vaccines using different host expression systems, aspects to consider in recombinant protein vaccine development, and overcoming problems associated with large-scale recombinant protein vaccine production. In silico approaches to identify conserved and immunogenic epitopes could provide broad protection against SARS-CoV-2 VOCs but require validation in animal models. The recombinant protein vaccine development platform has shown a successful history in clinical development. Recombinant protein vaccines incorporating conserved epitopes may utilize a number of expression systems, such as yeast (Saccharomyces cerevisiae), baculovirus-insect cells (Sf9 cells), and Escherichia coli (E. coli). Current multi-epitope subunit vaccines against SARS-CoV-2 utilizing synthetic peptides are unfeasible for large-scale immunizations. Recombinant protein vaccines based on conserved and immunogenic proteins produced using E. coli offer high production yields, convenient purification, and cost-effective production of large-scale vaccine quantities capable of protecting against the SARS-CoV-2 D614G strain and its VOCs.

Matched MeSH terms: Spike Glycoprotein, Coronavirus/immunology
Fulltext N-terminal domain of SARS CoV-2 spike protein mutation associated reduction in effectivity of neutralizing antibody with vaccinated individuals

Singh Y, Fuloria NK, Fuloria S, Subramaniyan V, Meenakshi DU, Chakravarthi S, et al.

J Med Virol, 2021 Oct;93(10):5726-5728.
PMID: 34232521 DOI: 10.1002/jmv.27181
Matched MeSH terms: Spike Glycoprotein, Coronavirus/immunology
Fulltext Structural Evaluation of the Spike Glycoprotein Variants on SARS-CoV-2 Transmission and Immune Evasion

Salleh MZ, Derrick JP, Deris ZZ

Int J Mol Sci, 2021 Jul 10;22(14).
PMID: 34299045 DOI: 10.3390/ijms22147425

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents significant social, economic and political challenges worldwide. SARS-CoV-2 has caused over 3.5 million deaths since late 2019. Mutations in the spike (S) glycoprotein are of particular concern because it harbours the domain which recognises the angiotensin-converting enzyme 2 (ACE2) receptor and is the target for neutralising antibodies. Mutations in the S protein may induce alterations in the surface spike structures, changing the conformational B-cell epitopes and leading to a potential reduction in vaccine efficacy. Here, we summarise how the more important variants of SARS-CoV-2, which include cluster 5, lineages B.1.1.7 (Alpha variant), B.1.351 (Beta), P.1 (B.1.1.28/Gamma), B.1.427/B.1.429 (Epsilon), B.1.526 (Iota) and B.1.617.2 (Delta) confer mutations in their respective spike proteins which enhance viral fitness by improving binding affinity to the ACE2 receptor and lead to an increase in infectivity and transmission. We further discuss how these spike protein mutations provide resistance against immune responses, either acquired naturally or induced by vaccination. This information will be valuable in guiding the development of vaccines and other therapeutics for protection against the ongoing coronavirus disease 2019 (COVID-19) pandemic.

Matched MeSH terms: Spike Glycoprotein, Coronavirus/immunology
Fulltext Immunogenicity, reactogenicity, and safety of a second booster with BNT162b2 or full-dose mRNA-1273: A randomized VACCELERATE trial in adults aged ≥75 years (EU-COVAT-1-AGED Part B)

Stemler J, Yeghiazaryan L, Stephan C, Mohn KG, Carcas-Sansuan AJ, Rodriguez ER, et al.

Int J Infect Dis, 2024 Sep;146:107161.
PMID: 38992789 DOI: 10.1016/j.ijid.2024.107161

OBJECTIVES: To assess the safety and immunogenicity of a fourth vaccination (second booster) in individuals aged ≥75 years.
METHODS: Participants were randomized to BNT162b2 (Comirnaty, 30 µg) or messenger RNA (mRNA)-1273 (Spikevax, 100 µg). The primary end point was the rate of two-fold antibody titer increase 14 days after vaccination, targeting the receptor binding domain (RBD) region of wild-type SARS-CoV-2. The secondary end points included changes in neutralizing activity against wild-type and 25 variants. Safety was assessed by monitoring solicited adverse events (AEs) for 7 days.
RESULTS: A total of 269 participants (mean age 81 years, mRNA-1273 n = 135/BNT162b2 n = 134) were included. Two-fold anti-RBD immunoglobulin (Ig) G titer increase was achieved by 101 of 129 (78%) and 116 of 133 (87%) subjects in the BNT162b2 and the mRNA-1273 group, respectively (P = 0.054). A second booster of mRNA-1273 provided higher anti-RBD IgG geometric mean titer: 21.326 IU/mL (95% confidence interval: 18.235-24.940) vs BNT162b2: 15.181 IU/mL (95% confidence interval: 13.172-17.497). A higher neutralizing activity was noted for the mRNA-1273 group. The most frequent AE was pain at the injection site (51% in mRNA-1273 and 48% in BNT162b2). Participants in the mRNA-1273 group had less vaccine-related AEs (30% vs 39%).
CONCLUSIONS: A second booster of either BNT162b2 or mRNA-1273 provided substantial IgG increase. Full-dose mRNA-1273 provided higher IgG levels and neutralizing capacity against SARS-CoV-2, with similar safety profile for subjects of advanced age.

Matched MeSH terms: Spike Glycoprotein, Coronavirus/immunology
Immunoinformatics-guided design of a conserved multi-epitope vaccine candidate against pathogenic human coronaviruses

Lim CP, Bingöl EN, Oliveira JIN, Chuah C, Khan MA, Douradinha B, et al.

Naunyn Schmiedebergs Arch Pharmacol, 2026 Oct;399(13):21391-21409.
PMID: 42484859 DOI: 10.1007/s00210-026-05714-x

Despite the global decline in COVID-19 incidence, the continued emergence of immune-evasive SARS-CoV-2 variants underscores the urgent need for next-generation vaccines capable of providing broad protection. To characterise and design a broad-spectrum recombinant multiepitope vaccine candidate against pathogenic human coronaviruses using an immunoinformatics approach. Conserved antigenic regions within the spike (S), nucleocapsid (N) and membrane (M) proteins were identified from multiple SARS-CoV-2 variants through multiple sequence alignment. High-affinity T-cell and B-cell epitopes were screened and assembled into recombinant vaccine construct (RVC). The RVC was evaluated for antigenicity, allergenicity, toxicity and physicochemical properties, followed by tertiary structure prediction and validation. Molecular docking with Toll-like receptor 3 (TLR-3) and molecular dynamics (MD) simulations with MM-GBSA binding free energy calculations were performed, alongside in silico immune simulation. The RVC comprised four HLA class I-restricted epitopes, 27 HLA class II-restricted epitopes and five linear B-cell epitopes, with predicted global population coverage of 99.99%. The construct demonstrated high antigenicity, non-allergenicity and favourable physicochemical stability. Molecular docking showed stable interaction with TLR-3, supported by MD simulations and a favourable MM-GBSA binding free energy of - 5.19 kcal/mol. In silico immune simulation predicted robust humoral and cellular immune responses, including sustained memory cell populations following three-dose immunisation. These computational findings support the RVC as a promising broad-spectrum human coronavirus vaccine candidate. However, experimental validation, including immunogenicity, safety and protective efficacy studies in relevant in vitro and in vivo models, is warranted to substantiate its translational applicability.

Matched MeSH terms: Spike Glycoprotein, Coronavirus/immunology
Fulltext Prospective Evaluation of Antibody Response post COVID-19 vaccination in older persons ≧ 60 years old (PEARL 60): A longitudinal 15-months study in a tertiary centre in Malaysia

Hasmukharay K, Verma AK, Aravindhan K, Alagappan PRS, Kamal AKM, Zulhaimi NS, et al.

PLoS One, 2026;21(2):e0340891.
PMID: 41666143 DOI: 10.1371/journal.pone.0340891

Older adults exhibit heterogeneous immune responses to COVID-19 vaccination, yet the relative contributions of age, comorbidity, vaccine platform, and infection history to antibody durability remain incompletely defined. Understanding these determinants is essential to inform booster strategies in ageing populations. We conducted a longitudinal observational study of 300 participants (250 aged ≥60 years and 50 younger controls) followed for up to 15 months. Anti-spike (anti-S) antibody responses were assessed at four event-anchored timepoints: ≤ 3 months post-primary vaccination (TP1), ~ 3 months post-first booster (TP2), 6-9 months post-first booster capturing waning immunity (TP3), and ≤3 months post-second booster where available (TP4). Multivariable log-linear regression models were used to identify independent determinants of antibody levels, with additional analyses stratified by infection status and vaccine platform. Among older adults, 78.8% had moderate-to-severe comorbidity burden, 40.0% were pre-frail, and only 16.8% received a second booster. At TP3, older age was associated with lower antibody levels in univariable analysis (GMR 0.81, 95% CI 0.68-0.97) but not after adjustment (aGMR 0.78, 95% CI 0.51-1.22, p = 0.279). Independent predictors of higher TP3 antibody levels included female sex (aGMR 1.24, 95% CI 1.02-1.51, p = 0.028), prior SARS-CoV-2 infection (aGMR 1.39, 95% CI 1.14-1.71, p = 0.001), and mRNA (aGMR 5.16, 95% CI 3.57-7.47, p=<0.001) or viral vector boosters (aGMR 6.05, 95% CI 4.03-9.08, p=<0.001), while renal disease was associated with lower responses (aGMR 0.71, 95% CI 0.54-0.94, p = 0.017). Similar associations were observed at TP4. Frailty and sarcopenia were not independently associated with antibody levels. Neutralising antibodies against Omicron were absent after primary vaccination and detected in only 25.9% of infection-naïve older adults after the first booster. Sustained humoral immunity following COVID-19 vaccination is driven primarily by vaccine platform and immune history rather than chronological age or geriatric syndromes alone. Waning immunity unmasks vulnerability in older adults, while low uptake of second boosters highlights a critical gap between immunological risk and vaccine utilisation. These findings support targeted, equity-focused booster strategies prioritising highly immunogenic platforms and high-risk older adults.

Matched MeSH terms: Spike Glycoprotein, Coronavirus/immunology
Fulltext Mixing versus matching booster vaccines: Longitudinal humoral immune kinetics against Omicron in a Malaysian cohort

Thundakattil AV, Prabhu R, Prabhu G, Mani M, De S, Soe HHK, et al.

Int J Infect Dis, 2026 Nov;172:109103.
PMID: 42697472 DOI: 10.1016/j.ijid.2026.109103

OBJECTIVES: The objective of our study was to evaluate the longitudinal humoral immune response following booster regimens in Malaysia during the Omicron outbreak.
METHODS: In this prospective cohort study, 268 healthcare professionals and medical students in Malaysia were followed up for 24 weeks following homologous (messenger ribonucleic acid [mRNA]-mRNA [mR-mR], viral vector-viral vector [VV-VV], inactivated virus-inactivated virus [IV-IV]) and heterologous (inactivated virus-mRNA [IV-mR], viral vector-mRNA [VV-mR]) booster vaccines. Of them, 190 recipients underwent a longitudinal immunogenicity study. Anti-spike (anti-S) immunoglobulin G (IgG) and anti-receptor-binding domain (anti-RBD) responses were assessed by the ADVIA Centaur severe acute respiratory syndrome coronavirus 2 chemiluminescent immunoassay followed by a surrogate virus neutralization test using the Omicron variant across all boosters.
RESULTS: Compared to homologous boosters, heterologous regimens, particularly the IV-mR booster, elicited significantly higher and sustained anti-S IgG and anti-RBD antibody (P < 0.0001) responses. Over 24 weeks, the heterologous IV-mR booster group had 100% seropositivity for anti-S IgG and anti-RBD antibodies; conversely, in the homologous (IV-IV) booster group, the seropositivity of anti-S IgG and anti-RBD antibodies decreased to 15.63% and 18.75%, respectively. Omicron virus-neutralizing was observed to be as high as 95.92% (IV-mR) and 83.87% (VV-mR) at week 24 after the heterologous booster, while virus neutralization was found to be as low as 9.38% in the IV-IV homologous booster. Age, gender, and ethnicity were not found to be confounding factors for antibody kinetics following a booster vaccine.
CONCLUSION: In conclusion, heterologous booster vaccines induced a superior prolonged humoral immune response against coronavirus disease 2019 infection.

Matched MeSH terms: Spike Glycoprotein, Coronavirus/immunology
Fulltext Protective Immunity against SARS Subunit Vaccine Candidates Based on Spike Protein: Lessons for Coronavirus Vaccine Development

Khalaj-Hedayati A

J Immunol Res, 2020;2020:7201752.
PMID: 32695833 DOI: 10.1155/2020/7201752

The recent outbreak of the novel coronavirus disease, COVID-19, has highlighted the threat that highly pathogenic coronaviruses have on global health security and the imminent need to design an effective vaccine for prevention purposes. Although several attempts have been made to develop vaccines against human coronavirus infections since the emergence of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) in 2003, there is no available licensed vaccine yet. A better understanding of previous coronavirus vaccine studies may help to design a vaccine for the newly emerged virus, SARS-CoV-2, that may also cover other pathogenic coronaviruses as a potentially universal vaccine. In general, coronavirus spike protein is the major antigen for the vaccine design as it can induce neutralizing antibodies and protective immunity. By considering the high genetic similarity between SARS-CoV and SARS-CoV-2, here, protective immunity against SARS-CoV spike subunit vaccine candidates in animal models has been reviewed to gain advances that can facilitate coronavirus vaccine development in the near future.

Matched MeSH terms: Spike Glycoprotein, Coronavirus/immunology*