Homologous or Heterologous Booster of Inactivated Vaccine Reduces SARS-CoV-2 Omicron Variant Escape from Neutralizing Antibodies

Hand, foot, and mouth disease (HFMD) commonly produces herpangina, but fatal neurological complications have been observed in children. Enterovirus 71 (EV-A71) and Coxsackievirus 16 (CV-A16) are the predominant viruses causing HFMD worldwide. With rising concern about HFMD outbreaks, there is a need for an effective vaccine against EV-A71 and CV-A16. Although an inactivated vaccine has been developed against EV-A71 in China, the inability of the inactivated vaccine to confer protection against CV-A16 infection and other HFMD etiological agents, such as CV-A6 and CV-A10, necessitates the exploration of other vaccine platforms. Thus, the antigenic peptide-based vaccines are promising platforms to develop safe and efficacious multivalent vaccines, while the monoclonal antibodies are viable therapeutic and prophylactic agents against HFMD etiological agents. This article reviews the available information related to the antigenic peptides of the etiological agents of HFMD and their neutralizing antibodies that can provide a basis for the design of future therapies against HFMD etiological agents.

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Induction of IBV strain-specific neutralizing antibodies and broad spectrum protection in layer pullets primed with IBV Massachusetts (Mass) and 793B vaccines prior to injection of inactivated vaccine containing Mass antigen

Avian Pathology ◽

10.1080/03079457.2018.1556778 ◽

2019 ◽

Vol 48 (2) ◽

pp. 135-147 ◽

Cited By ~ 7

Author(s):

J. J. (Sjaak) de Wit ◽

Aris Malo ◽

Jane K. A. Cook

Keyword(s):

Broad Spectrum ◽

Neutralizing Antibodies ◽

Inactivated Vaccine

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A booster dose of an inactivated vaccine increases neutralizing antibodies and T cell responses against SARS-CoV-2

10.1101/2021.11.16.21266350 ◽

2021 ◽

Author(s):

Barbara M Schultz ◽

Felipe Melo-Gonzalez ◽

Luisa F Duarte ◽

Nicolas MS Galvez ◽

Gaspar A Pacheco ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Cellular Response ◽

Booster Dose ◽

Vaccination Schedule ◽

World Health ◽

Inactivated Vaccine ◽

Protective Capacity ◽

Cell Responses ◽

Health Organization ◽

Chilean Population

Numerous vaccines have been generated to decrease the morbidity and mortality of COVID-19. CoronaVac® is an inactivated SARS-CoV-2 vaccine approved by the World Health Organization (WHO) to prevent COVID-19 that has safety and immunogenicity profiles described in different clinical trials. We previously reported an increase in levels of neutralizing antibodies two- and four-weeks after administering two doses of CoronaVac® in a two-week interval (0-14 day) vaccination schedule, as compared to pre-immune sera in adults in the Chilean population that are participating in phase 3 clinical trial. Here we report the levels of antibodies directed against the Receptor Binding Domain of the SARS-CoV-2 spike protein comparing their neutralizing capacities and the cellular response at five months after the second dose and four weeks after a booster (third) dose in volunteers immunized with two doses of CoronaVac®in a four-week interval (0-28 day) vaccination schedule. We observed a decrease in the levels of anti-SARS-CoV-2 antibodies with neutralizing capacities five months after the second dose (GMU 39.0 95% confidence interval (CI)(32.4-47.0), which increased up to 12 times at four weeks after the booster dose (GMU 499.4, 95% CI=370.6-673.0). Equivalent results were observed in adults aged 18-59 years old and individuals ≥60 years old. In the case of cellular response, we observed that activation of specific CD4+ T cells increases in time and reaches its maximum at four weeks after the booster dose in both groups. Our results support the notion that a booster dose of the SARS-CoV-2 inactivated vaccine increases the levels of neutralizing antibodies and the specific cellular response in adults of both groups, which is likely to boost the protective capacity of these vaccines against COVID-19.

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Safety and immunogenicity evaluation of inactivated whole-virus-SARS-COV-2 as emerging vaccine development in Egypt

Antibody Therapeutics ◽

10.1093/abt/tbab012 ◽

2021 ◽

Author(s):

Amani A Saleh ◽

Mohamed A Saad ◽

Islam Ryan ◽

Magdy Amin ◽

Mohamed I Shindy ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Vaccine Development ◽

Clinical Symptoms ◽

Neutralizing Antibody ◽

Positive Development ◽

Effective Vaccine ◽

Inactivated Vaccine ◽

Virus Challenge ◽

Transmission Electron ◽

Dose Concentration

Abstract Background Current worldwide pandemic COVID-19 with high numbers of mortality rates and huge economic problems require an urgent demand for safe and effective vaccine development. Inactivated SARS-CoV2 vaccine with alum. Hydroxide can play an important role in reducing the impacts of the COVID-19 pandemic. In this study, vaccine efficacy was evaluated through the detection of the neutralizing antibodies that protect mice from challenge with SARS-CoV 2 three weeks after the 2nd dose. We conclude that the vaccine described here has safety and desirable properties, and our data support further development and plans for clinical trials. Methods Characterized SARS-COV-2 strain, severe acute respiratory syndrome coronavirus 2 isolates (SARS-CoV-2/human/EGY/Egy-SERVAC/2020) with accession numbers; MT981440; MT981439; MT981441; MT974071; MT974069, and MW250352 at GenBank were isolated from Egyptian patients SARS-CoV-2-positive. Development of inactivated vaccine was carried out in a BSL—3 facilities and the immunogenicity was determined in mice at two doses (55 μg and 100 μg per dose). Results The distinct cytopathic effect (CPE) induced by SARS-COV-2 propagation on Vero cell monolayers and the viral particles were identified as Coronaviridae by transmission electron microscopy and RT-PCR on infected cells cultures. Immunogenicity of the developed vaccine indicated the high antigen-binding and neutralizing antibody titers, regardless of the dose concentration, with excellent safety profiles and no deaths or clinical symptoms in mice groups. The efficacy of the inactivated vaccine formulation was tested by the wild virus challenge of the vaccinated mice and viral replication detection in lung tissues. Conclusions Vaccinated mice recorded complete protection from challenge infection via inhibition of SARS-COV-2 replication in the lung tissues of mice following virus challenge, regardless of the level of serum neutralizing antibodies. This finding will support future trials for the evaluation of an applicable SARS-CoV-2 vaccine candidate.

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Robust induction of B cell and T cell responses by a third dose of inactivated SARS-CoV-2 vaccine

10.1101/2021.09.12.21263373 ◽

2021 ◽

Cited By ~ 1

Author(s):

Yihao Liu ◽

Qin Zeng ◽

Caiguanxi Deng ◽

Mengyuan Li ◽

Liubing Li ◽

...

Keyword(s):

T Cells ◽

Neutralizing Antibodies ◽

Vaccination Schedule ◽

Immune Memory ◽

Severe Illness ◽

Inactivated Vaccine ◽

Serological Response ◽

Humoral Immune ◽

The Third

AbstractSARS-CoV-2 inactivated vaccines have shown remarkable efficacy in clinical trials, especially in reducing severe illness and casualty. However, the waning of humoral immunity over time has raised concern over the durability of immune memory following vaccination. Thus, we conducted a non-randomized trial among the healthcare professionals (HCWs) to investigate the long-term sustainability of SARS-CoV-2-specific B cells and T cells stimulated by inactivated vaccine and the potential need for a third booster dose for the HCWs. Although neutralizing antibodies elicited by the standard two-dose vaccination schedule dropped from a peak of 31.2 AU/ml to 9.2 AU/ml 5 months after the second vaccination, spike-specific memory B and T cells were still detectable, forming the basis for a quick recall response. As expected, the faded humoral immune response was vigorously elevated to 66.8 AU/ml by 7.2 folds 1 week after the third dose along with abundant spike-specific circulating follicular helper T cells in parallel. Meanwhile, spike-specific CD4+ and CD8+ T cells were also robustly elevated by 5.9 and 2.7 folds respectively. Robust expansion of memory pools by the third dose potentiated greater durability of protective immune responses. Another key finding in this trial was that HCWs with low serological response to 2 doses were not truly “no responders” but fully equipped with immune memory that could be quickly recalled by a third dose even 5 months after the second vaccination. Collectively, these data provide insights into the generation of long-term immunological memory by the inactivated vaccine, which has implications for future booster strategies that the frontline HCWs, individuals with low serological response to 2 dose of vaccine and immune compromised patients could benefit from a third dose of inactivated vaccine.

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A valid protective immune response elicited in rhesus macaques by an inactivated vaccine is capable of defending against SARS-CoV-2 infection

10.1101/2020.08.04.235747 ◽

2020 ◽

Cited By ~ 3

Author(s):

Hongbo Chen ◽

Zhongping Xie ◽

Runxiang Long ◽

Shengtao Fan ◽

Heng Li ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Rhesus Macaques ◽

Peptide Vaccine ◽

Inflammatory Lesion ◽

Neutralizing Antibody ◽

Inactivated Vaccine ◽

Structural Protein ◽

Global Epidemic ◽

Antibody Titers ◽

Therapeutic Measures

AbstractWith the relatively serious global epidemic outbreak of SARS-CoV-2 infection, public concerns focus on not only clinical therapeutic measures and public quarantine for this disease but also the development of vaccines. The technical design of our SARS-CoV-2 inactivated vaccine provides a viral antigen that enables the exposure of more than one structural protein based upon the antibody composition of COVID-19 patients’ convalescent serum. This design led to valid immunity with increasing neutralizing antibody titers and a CTL response detected post-immunization of this vaccine by two injections in rhesus macaques. Further, this elicited immunoprotection in macaques enables not only to restrain completely viral replication in tissues of immunized animals, compared to the adjuvant control and those immunized by an RBD peptide vaccine, but also to significantly alleviate inflammatory lesion in lung tissues in histo-pathologic detection, compared to the adjuvant control with developed interstitial pneumonia. The data obtained from these macaques immunized with the inactivated vaccine or RBD peptide vaccine suggest that immunity with a clinically protective effect against SARS-CoV-2 infection should include not only specific neutralizing antibodies but also specific CTL responses against at least the S and N antigens.

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Homologous or Heterologous Booster of Inactivated Vaccine Reduces SARS-CoV-2 Omicron Variant Escape from Neutralizing Antibodies

10.1101/2021.12.24.474138 ◽

2021 ◽

Author(s):

Xun Wang ◽

Xiaoyu Zhao ◽

Jieyu Song ◽

Jing Wu ◽

Yuqi Zhu ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Subunit Vaccine ◽

Booster Vaccination ◽

Neutralizing Antibody ◽

Inactivated Vaccine ◽

Protein Subunit ◽

The Third ◽

Vaccine Booster ◽

Push Forward ◽

Rapid Transmission

The massive and rapid transmission of SARS-CoV-2 has led to the emergence of several viral variants of concern (VOCs), with the most recent one, B.1.1.529 (Omicron), which accumulated a large number of spike mutations, raising the specter that this newly identified variant may escape from the currently available vaccines and therapeutic antibodies. Using VSV-based pseudovirus, we found that Omicron variant is markedly resistant to neutralization of sera form convalescents or individuals vaccinated by two doses of inactivated whole-virion vaccines (BBIBP-CorV). However, a homologous inactivated vaccine booster or a heterologous booster with protein subunit vaccine (ZF2001) significantly increased neutralization titers to both WT and Omicron variant. Moreover, at day 14 post the third dose, neutralizing antibody titer reduction for Omicron was less than that for convalescents or individuals who had only two doses of the vaccine, indicating that a homologous or heterologous booster can reduce the Omicron escape from neutralizing. In addition, we tested a panel of 17 SARS-CoV-2 monoclonal antibodies (mAbs). Omicron resists 7 of 8 authorized/approved mAbs, as well as most of the other mAbs targeting distinct epitopes on RBD and NTD. Taken together, our results suggest the urgency to push forward the booster vaccination to combat the emerging SARS-CoV-2 variants.

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Safety and immunogenicity of a heterologous boost with a recombinant vaccine, NVSI-06-07, in the inactivated vaccine recipients from UAE: a phase 2 randomised, double-blinded, controlled clinical trial

10.1101/2021.12.29.21268499 ◽

2022 ◽

Author(s):

Nawal AlKaabi ◽

Yun Kai Yang ◽

Jing Zhang ◽

Ke Xu ◽

Yu Liang ◽

...

Keyword(s):

United Arab Emirates ◽

Neutralizing Antibodies ◽

Geometric Mean ◽

Prototype Strain ◽

Controlled Clinical Trial ◽

Inactivated Vaccine ◽

Phase 2 ◽

Significant Difference ◽

Double Blinded ◽

Heterologous Boost

Background: The increased coronavirus disease 2019 (COVID-19) breakthrough cases pose the need of booster vaccinations. In this study, we reported the safety and immunogenicity of a heterologous boost with a recombinant COVID-19 vaccine (CHO cells), named NVSI-06-07, as a third dose in participants who have previously received two doses of the inactivated vaccine (BBIBP-CorV) at pre-specified time intervals. Using homologous boost with BBIBP-CorV as control, the safety and immunogenicity of the heterologous boost with NVSI-06-07 against various SARS-CoV-2 strains, including Omicron, were characterized. Methods: This study is a single-center, randomised, double-blinded, controlled phase 2 trial for heterologous boost of NVSI-06-07 in BBIBP-CorV recipients from the United Arab Emirates (UAE). Healthy adults (aged ≥18 years) were enrolled and grouped by the specified prior vaccination interval of BBIBP-CorV, i.e., 1-3 months, 4-6 months or ≥6 months, respectively, with 600 individuals per group. For each group, participants were randomly assigned at 1:1 ratio to receive either a heterologous boost of NVSI-06-07 or a homologous booster dose of BBIBP-CorV. The primary outcome was to comparatively assess the immunogenicity between heterologous and homologous boosts at 14 and 28 days post-boosting immunization, by evaluation of the geometric mean titers (GMTs) of IgG and neutralizing antibodies as well as the corresponding seroconversion rate (≥4-fold rise in antibody titers). The secondary outcomes were the safety profile of the boosting strategies within 30 days post vaccination. The exploratory outcome was the immune efficacy against Omicron and other variants of concern (VOCs) of SARS-CoV-2. This trial is registered with ClinicalTrials.gov, NCT05033847. Findings: A total of 1800 individuals who have received two doses of BBIBP-CorV were enrolled, of which 899 participants received a heterologous boost of NVSI-06-07 and 901 received a homologous boost for comparison. No vaccine-related serious adverse event (SAE) and no adverse events of special interest (AESI) were reported. 184 (20.47%) participants in the heterologous boost groups and 177 (19.64%) in the homologous boost groups reported at least one adverse reaction within 30 days. Most of the local and systemic adverse reactions reported were grades 1 (mild) or 2 (moderate), and there was no significant difference in the overall safety between heterologous and homologous boosts. Immunogenicity assays showed that the seroconversion rates in neutralizing antibodies against prototype SARS-CoV-2 elicited by heterologous boost were 89.96% - 97.52% on day 28 post-boosting vaccination, which was much higher than what was induced by homologous boost (36.80% - 81.75%). Similarly, in heterologous NVSI-06-07 booster groups, the neutralizing geometric mean titers (GMTs) against the prototype strain increased by 21.01 - 63.85 folds from baseline to 28 days post-boosting vaccination, whereas only 4.20 - 16.78 folds of increases were observed in homologous BBIBP-CorV booster group. For Omicron variant, the neutralizing antibody GMT elicited by the homologous boost of BBIBP-CorV was 37.91 (95%CI, 30.35-47.35), however, a significantly higher level of neutralizing antibodies with GMT 292.53 (95%CI, 222.81-384.07) was induced by the heterologous boost of NVSI-06-07, suggesting that it may serve as an effective boosting strategy combating the pandemic of Omicron. The similar results were obtained for other VOCs, including Alpha, Beta and Delta, in which the neutralizing response elicited by the heterologous boost was also significantly greater than that of the homologous boost. In the participants primed with BBIBP-CorV over 6 months, the largest increase in the neutralizing GMTs was obtained both in the heterologous and homologous boost groups, and thus the booster vaccination with over 6 months intervals was optimal. Interpretation: Our findings indicated that the heterologous boost with NVSI-06-07 was safe, well-tolerated and immunogenic in adults primed with a full regimen of BBIBP-CorV. Compared to homologous boost with a third dose of BBIBP-CorV, incremental increases in immune responses were achieved by the heterologous boost with NVSI-06-07 against SARS-CoV-2 prototype strain, Omicron variant, and other VOCs. The heterologous BBIBP-CorV/NVSI-06-07 prime-boosting vaccination may be valuable in preventing the pandemic of Omicron. The optimal booster strategy was the heterologous boost with NVSI-06-07 over 6 months after a priming with two doses of BBIBP-CorV.

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Early immune response in mice immunized with a semi-split inactivated vaccine against SARS-CoV-2 containing S protein-free particles and subunit S protein

10.1101/2020.11.03.366641 ◽

2020 ◽

Author(s):

Marek Petráš ◽

Petr Lesný ◽

Jan Musil ◽

Radomíra Limberková ◽

Alžběta Pátíková ◽

...

Keyword(s):

Cellular Immunity ◽

Neutralizing Antibodies ◽

Immune Cell ◽

Geometric Mean ◽

Inactivated Vaccine ◽

S Protein ◽

Humoral And Cellular Immunity ◽

Wide Range ◽

Immune Cell Response ◽

Th1 And Th2 Lymphocytes

AbstractThe development of a vaccine against COVID-19 is a hot topic for many research laboratories all over the world. Our aim was to design a semi-split inactivated vaccine offering a wide range of multi-epitope determinants important for the immune system including not only the spike (S) protein but also the envelope, membrane and nucleocapsid proteins. We designed a semi-split vaccine prototype consisting of S protein-depleted viral particles and free S protein. Next, we investigated its immunogenic potential in BALB/c mice. The animals were immunized intradermally or intramuscularly with the dose adjusted with buffer or addition of aluminum hydroxide, respectively. The antibody response was evaluated by plasma analysis at 7 days after the first or second dose. The immune cell response was studied by flow cytometry analysis of splenocytes. The data showed a very early onset of both S protein-specific antibodies and virus-neutralizing antibodies at 90% inhibition regardless of the route of vaccine administration. However, significantly higher levels of neutralizing antibodies were detected in the intradermally (geometric mean titer - GMT of 7.8 ± 1.4) than in the intramuscularly immunized mice (GMT of 6.2 ± 1.5). In accordance with this, stimulation of cellular immunity by the semi-split vaccine was suggested by elevated levels of B and T lymphocyte subpopulations in the murine spleens. These responses were more predominant in the intradermally immunized mice compared with the intramuscular route of administration. The upward trend in the levels of plasmablasts, memory B cells, Th1 and Th2 lymphocytes, including follicular helper T cells, was confirmed even in mice receiving the vaccine intradermally at a dose of 0.5 μg.We demonstrated that the semi-split vaccine is capable of eliciting both humoral and cellular immunity early after vaccination. Our prototype thus represents a promising step toward the development of an efficient anti-COVID-19 vaccine for human use.

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