Influenza, SARS-CoV-2, RSV and Other Vaccines: Immunogenicity Parameters and Protection, 3rd Edition

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: 30 May 2025 | Viewed by 12306

Special Issue Editor

Special Issue Information

Dear Colleagues,

During the assessment and licensing of novel vaccines and in the post-licensure follow up, it is critical to have reliable immunogenicity-testing methods that relate well to protection. The need for reliable immunogenicity criteria became apparent in the preparation for the potential pandemic threat posed by influenza A H5N1 in 2006, when great intra- and interlaboratory variations were seen for hemagglutinin inhibition and microneutralization tests, and the need for a centralized standard was acknowledged by the WHO and NIBSC.

In the case of SARS-CoV-2, this remains a critical issue, as many different antibody tests have been developed urgently, but with unknown correlation to real-world protection. Therefore, collaboration among different laboratories and health authorities is essential to establish standards, reduce interlaboratory variations, and establish immunogenicity correlates that can be used for licensing as well as patient care. In this Special Issue, we seek papers discussing the development of reliable immunogenicity tests that correlate with real-world protection against SARS-CoV-2, influenza, respiratory syncytial virus (RSV), and other novel vaccines.

Sub-topics: antibody levels; cellular immunity; correlates of protection; rapid vs. laboratory antibody kits; the role of ELISA.

Dr. Zoltan Vajo
Guest Editor

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Keywords

  • SARS-CoV-2
  • serology
  • cellular immune response
  • protection
  • vaccines
  • influenza
  • Respiratory Syncytial Virus (RSV)

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Published Papers (7 papers)

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Research

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10 pages, 663 KiB  
Article
Effectiveness of Inactivated Coronavirus Disease 2019 Vaccine Against Omicron BA.2.2 Infection in Beijing, China, 2022: A Cohabitation Retrospective Cohort Study
by Shuaibing Dong, Ying Sun, Zhaomin Feng, Yi Tian, Lei Jia, Xiaoli Wang, Quanyi Wang, Daitao Zhang and Peng Yang
Viruses 2025, 17(1), 31; https://doi.org/10.3390/v17010031 - 28 Dec 2024
Cited by 1 | Viewed by 1135
Abstract
The present study aimed to evaluate the vaccine effectiveness (VE) of different doses of an inactivated coronavirus disease 2019 (COVID-19) vaccine against Omicron BA.2.2 infection in Beijing, China, 2022. Based on data from a previous cohabitation retrospective cohort of COVID-19 outbreak in Beijing, [...] Read more.
The present study aimed to evaluate the vaccine effectiveness (VE) of different doses of an inactivated coronavirus disease 2019 (COVID-19) vaccine against Omicron BA.2.2 infection in Beijing, China, 2022. Based on data from a previous cohabitation retrospective cohort of COVID-19 outbreak in Beijing, China, 2022, the cohabitating contacts of individuals with BA.2.2 infection were followed up. Using a log-binomial regression model in which the unvaccinated group as the control group, the risk ratios of different doses of inactivated vaccine in terms of preventing SARS-CoV-2 infection, symptoms of COVID-19, and pneumonia were calculated, and the protective effect of the vaccine was estimated. The Kruskal–Wallis rank-sum test was used to compare the effect of vaccination on the viral load of infected patients. From April to June 2022, a total of 2259 cohabiting close contacts of 1308 patients with SARS-CoV-2 infection aged ≥3 years were included. Of the included close contacts, 737 (32.63%) were positive for SARS-CoV-2 during the isolation period: 140 (19.00%) were infected but asymptomatic, 525 (71.23%) had mild infection, and 72 (9.77%) had pneumonia. There were no cases of severe or critical infection or death. The VE of the primary in preventing BA.2.2 infection, symptoms, and pneumonia was 37.35% (95% CI: 24.00–48.35), 42.36% (95% CI: 28.41–53.60), and 48.35% (95% CI: −5.34–74.67), respectively. The VE of the booster shot in preventing SARS-CoV-2 infection, symptoms, and pneumonia was 37.08% (95% CI: 24.29–47.70), 44.38% (95% CI: 31.45–54.87), and 61.46% (95% CI: 29.79–78.85), respectively. Six months after the booster vaccination, the VE of the booster in terms of preventing SARS-CoV-2 remained above 46%, and its VE in terms of the prevention of pneumonia remained above 72%. In the unvaccinated group, the Ct values of the N gene and ORFlab gene (represented by the median value and Q1 and Q3 in parentheses) were 26.45 (21.09, 31.61) and 28.06 (22.21, 32.06), respectively. There was no significant difference in the median value of either gene between the unvaccinated group, the partial group [25.81 (19.91, 31.78) and 26.98 (21.63, 31.17)], the primary group [28.79 (22.08, 32.34) and 29.30 (23.81, 33.86)], and the booster group [26.23 (21.66, 31.46) and 27.73 (23.38, 32.52)] (p > 0.05). Inactivated COVID-19 vaccines provided a certain level protection from infection and symptoms, very good protection against pneumonia, and it still has a modest protective effect at 6 months after vaccination. Booster doses are necessary to provide strongest protection. However, irrespective of their vaccination status, individuals with COVID-19 have a similar viral load. Full article
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12 pages, 2665 KiB  
Article
Development and Validation of an Enzyme-Linked Immunosorbent Assay-Based Protocol for Evaluation of Respiratory Syncytial Virus Vaccines
by Eliel Nham, A-Yeung Jang, Hyun Jung Ji, Ki Bum Ahn, Joon-Yong Bae, Man-Seong Park, Jin Gu Yoon, Hye Seong, Ji Yun Noh, Hee Jin Cheong, Woo Joo Kim, Ho Seong Seo and Joon Young Song
Viruses 2024, 16(6), 952; https://doi.org/10.3390/v16060952 - 12 Jun 2024
Cited by 1 | Viewed by 2033
Abstract
Recently, respiratory syncytial virus (RSV) vaccines based on the prefusion F (pre-F) antigen were approved in the United States. We aimed to develop an enzyme-linked immunosorbent assay (ELISA)-based protocol for the practical and large-scale evaluation of RSV vaccines. Two modified pre-F proteins (DS-Cav1 [...] Read more.
Recently, respiratory syncytial virus (RSV) vaccines based on the prefusion F (pre-F) antigen were approved in the United States. We aimed to develop an enzyme-linked immunosorbent assay (ELISA)-based protocol for the practical and large-scale evaluation of RSV vaccines. Two modified pre-F proteins (DS-Cav1 and SC-TM) were produced by genetic recombination and replication using an adenoviral vector. The protocol was established by optimizing the concentrations of the coating antigen (pre-F proteins), secondary antibodies, and blocking buffer. To validate the protocol, we examined its accuracy, precision, and specificity using serum samples from 150 participants across various age groups and the standard serum provided by the National Institute of Health. In the linear correlation analysis, coating concentrations of 5 and 2.5 μg/mL of DS-Cav1 and SC-TM showed high coefficients of determination (r > 0.90), respectively. Concentrations of secondary antibodies (alkaline phosphatase-conjugated anti-human immunoglobulin G, diluted 1:2000) and blocking reagents (5% skim milk/PBS-T) were optimized to minimize non-specific reactions. High accuracy was observed for DS-Cav1 (r = 0.90) and SC-TM (r = 0.86). Further, both antigens showed high precision (coefficient of variation < 15%). Inhibition ELISA revealed cross-reactivity of antibodies against DS-Cav1 and SC-TM, but not with the attachment (G) protein. Full article
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23 pages, 4971 KiB  
Article
Intranasal Vaccination with a Respiratory-Syncytial-Virus-Based Virus-like Particle Displaying the G Protein Conserved Region Induces Severe Weight Loss and Pathology upon Challenge with Wildtype Respiratory Syncytial Virus
by Megolhubino Terhüja, Manjunath Siddappa, Pramila Lamichhane, Chetan D. Meshram, Timothy A. Snider, Jerry W. Ritchey and Antonius G. P. Oomens
Viruses 2024, 16(6), 843; https://doi.org/10.3390/v16060843 - 24 May 2024
Cited by 1 | Viewed by 2194
Abstract
Respiratory syncytial virus (RSV) is a major cause of severe respiratory tract disease worldwide, and a pediatric vaccine is not available. We generated a filamentous RSV-based virus-like particle (VLP) that presents the central conserved region of the attachment protein G. This was achieved [...] Read more.
Respiratory syncytial virus (RSV) is a major cause of severe respiratory tract disease worldwide, and a pediatric vaccine is not available. We generated a filamentous RSV-based virus-like particle (VLP) that presents the central conserved region of the attachment protein G. This was achieved by co-expressing the matrix protein, phosphoprotein, nucleoprotein, and a hybrid fusion protein in which the F ectodomain was replaced with the G central region (GCR). The latter is relatively conserved and contains a receptor binding site and hence is a logical vaccine target. The immunogenicity and efficacy of the resulting VLP, termed VLP-GCR, were examined in mice using intranasal application without adjuvant. VLP-GCR induced substantial anti-N antibody levels but very low anti-G antibody levels, even after three vaccinations. In contrast, a VLP presenting prefusion-stabilized fusion (preF) protein instead of GCR induced both high anti-F and anti-nucleoprotein antibody levels, suggesting that our GCR antigen was poorly immunogenic. Challenge of VLP-GCR-vaccinated mice caused increased weight loss and lung pathology, and both VLPs induced mucus in the lungs. Thus, neither VLP is suitable as a vaccine for RSV-naive individuals. However, VLP-preF enhanced the proportion of preF antibodies and could serve as a multi-antigen mucosal booster vaccine in the RSV-experienced population. Full article
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17 pages, 2701 KiB  
Article
SARS-CoV-2-Specific Immune Responses in Vaccination and Infection during the Pandemic in 2020–2022
by Wakana Inoue, Yuta Kimura, Shion Okamoto, Takuto Nogimori, Akane Sakaguchi-Mikami, Takuya Yamamoto and Yasuko Tsunetsugu-Yokota
Viruses 2024, 16(3), 446; https://doi.org/10.3390/v16030446 - 13 Mar 2024
Viewed by 1952
Abstract
To gain insight into how immunity develops against SARS-CoV-2 from 2020 to 2022, we analyzed the immune response of a small group of university staff and students who were either infected or vaccinated. We investigated the levels of receptor-binding domain (RBD)-specific and nucleocapsid [...] Read more.
To gain insight into how immunity develops against SARS-CoV-2 from 2020 to 2022, we analyzed the immune response of a small group of university staff and students who were either infected or vaccinated. We investigated the levels of receptor-binding domain (RBD)-specific and nucleocapsid (N)-specific IgG and IgA antibodies in serum and saliva samples taken early (around 10 days after infection or vaccination) and later (around 1 month later), as well as N-specific T-cell responses. One patient who had been infected in 2020 developed serum RBD and N-specific IgG antibodies, but declined eight months later, then mRNA vaccination in 2021 produced a higher level of anti-RBD IgG than natural infection. In the vaccination of naïve individuals, vaccines induced anti-RBD IgG, but it declined after six months. A third vaccination boosted the IgG level again, albeit to a lower level than after the second. In 2022, when the Omicron variant became dominant, familial transmission occurred among vaccinated people. In infected individuals, the levels of serum anti-RBD IgG antibodies increased later, while anti-N IgG peaked earlier. The N-specific activated T cells expressing IFN γ or CD107a were detected only early. Although SARS-CoV-2-specific salivary IgA was undetectable, two individuals showed a temporary peak in RBD- and N-specific IgA antibodies in their saliva on the second day after infection. Our study, despite having a small sample size, revealed that SARS-CoV-2 infection triggers the expected immune responses against acute viral infections. Moreover, our findings suggest that the temporary mucosal immune responses induced early during infection may provide better protection than the currently available intramuscular vaccines. Full article
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Review

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19 pages, 323 KiB  
Review
The Development of Animal Models for Respiratory Syncytial Virus (RSV) Infection and Enhanced RSV Disease
by Gengxin Zhang, Binbin Zhao and Jiangning Liu
Viruses 2024, 16(11), 1701; https://doi.org/10.3390/v16111701 - 30 Oct 2024
Viewed by 1934
Abstract
The development of immunoprophylactic products against respiratory syncytial virus (RSV) has resulted in notable advancements, leading to an increased demand for preclinical experiments and placing greater demands on animal models. Nevertheless, the field of RSV research continues to face the challenge of a [...] Read more.
The development of immunoprophylactic products against respiratory syncytial virus (RSV) has resulted in notable advancements, leading to an increased demand for preclinical experiments and placing greater demands on animal models. Nevertheless, the field of RSV research continues to face the challenge of a lack of ideal animal models. Despite the demonstration of efficacy in animal studies, numerous RSV vaccine candidates have been unsuccessful in clinical trials, primarily due to the lack of suitable animal models. The most commonly utilized animal models for RSV research are cotton rats, mice, lambs, and non-human primates. These animals have been extensively employed in mechanistic studies and in the development and evaluation of vaccines and therapeutics. However, each model only exemplifies some, but not all, aspects of human RSV disease. The aim of this study was to provide a comprehensive summary of the disease symptoms, viral replication, pathological damage, and enhanced RSV disease (ERD) conditions across different RSV animal models. Furthermore, the advantages and disadvantages of each model are discussed, with the intention of providing a valuable reference for related RSV research. Full article

Other

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9 pages, 406 KiB  
Brief Report
Evaluation of Humoral and Cell-Mediated Immunity Induced by Quadrivalent Influenza Vaccine in Pre-COVID-19 Japan
by Naruhito Otani, Toshiomi Okuno, Kumiko Yamada, Toshie Tsuchida, Kaori Ishikawa, Kaoru Ichiki, Takashi Ueda, Yoshio Takesue, Satoshi Higasa and Kazuhiko Nakajima
Viruses 2025, 17(5), 626; https://doi.org/10.3390/v17050626 (registering DOI) - 26 Apr 2025
Viewed by 131
Abstract
This study aimed to evaluate the humoral and cell-mediated immune responses induced by an inactivated influenza vaccine (IIV4) during the 2019/2020 influenza season in Japan. We collected blood samples from 25 healthy adults before vaccination, 2 weeks post-vaccination, and 5 months post-vaccination. Humoral [...] Read more.
This study aimed to evaluate the humoral and cell-mediated immune responses induced by an inactivated influenza vaccine (IIV4) during the 2019/2020 influenza season in Japan. We collected blood samples from 25 healthy adults before vaccination, 2 weeks post-vaccination, and 5 months post-vaccination. Humoral and cell-mediated immunities were assessed based on hemagglutination inhibition antibody titers and interferon-γ (IFN-γ) levels, respectively. The geometric mean titer ratio for A/H3N2 exceeded 2.5, meeting the criteria outlined by the European Medicines Agency guidelines; other strains did not achieve similar thresholds. IFN-γ responses indicated significant activation for all strains, with 32–36% of participants exhibiting ≥ 1.5-fold increases. Due to the implementation of infection control measures against COVID-19, influenza activity was not observed during the 2020/2021 and 2021/2022 seasons, potentially altering influenza immunity. Our findings highlight the importance of both humoral and cell-mediated immunity in evaluating vaccine immunogenicity. Full article
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7 pages, 214 KiB  
Perspective
Developing Correlates of Protection for Vaccines Is Needed More than Ever—Influenza, COVID-19 and RSV Infection
by Zoltan Vajo and Csaba Laszlofy
Viruses 2024, 16(11), 1671; https://doi.org/10.3390/v16111671 - 25 Oct 2024
Viewed by 1511
Abstract
One of the greatest success stories of modern medicine is the prevention of infectious diseases by vaccination, most notably against smallpox and poliomyelitis. However, recent events, such as the 2009–2010 swine flu and the 2020 COVID-19 pandemics, as well as the continued emergence [...] Read more.
One of the greatest success stories of modern medicine is the prevention of infectious diseases by vaccination, most notably against smallpox and poliomyelitis. However, recent events, such as the 2009–2010 swine flu and the 2020 COVID-19 pandemics, as well as the continued emergence of highly pathogenic avian influenza viruses highlighted the fact that we still need to develop new vaccines, and perhaps we should be proactive, rather than reacting to epidemics and pandemics. However, the development of tools for evaluating novel vaccines has not been able to keep up with the rate of vaccine production. Humoral and cellular immune responses to vaccination have both been suggested to be important in preventing infections or ameliorating their consequences, although there is uncertainty regarding their exact roles and importance. This, together with the rapid development of new vaccines, means that the need for developing immunogenicity parameters, and even more importantly, reliable correlates of protection, is more important than ever. Full article
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