The SARS-CoV-2 spike L452R-E484Q co-variant in the Indian B.1.617 strain Showed Significant Reduction in the Neutralization Activity of Immune Sera

Abstract To assess the impact of the key non-synonymous amino acid substitutions in the RBD of the spike protein of SARS-CoV-2 variant B.1.617.1 (dominant variant identified in the current India outbreak) on the infectivity and neutralization activities of the immune sera, L452R and E484Q (L452R-E484Q, “co-variant”) pseudotyped virus was constructed (with the D614G background). The impact on the binding with the neutralizing antibodies was also assessed by an ELISA assay. Pseudotyped virus carrying a L452R-E484Q co-variant showed a comparable infectivity compared with D614G. However, there was a significant reduction in the neutralization activity of the immune sera from non-human primates vaccinated with a recombinant Receptor binding domain (RBD) protein, convalescent patients, and healthy vaccinees vaccinated with an mRNA vaccine. In addition, there was a reduction in the binding of L452R-E484Q-D614G protein to the antibodies of the immune sera from vaccinated non-human primates. These results highlight the interplay between infectivity and other biologic factors involved in the natural evolution of SARS-CoV-2. Reduced neutralization activities against the L452R-E484Q co-variant will have impact to the health authorities planning and implications to the vaccination strategy/new vaccine development.

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Evidence of antigenic imprinting in sequential Sarbecovirus immunization

10.1101/2020.10.14.339465 ◽

2020 ◽

Author(s):

Huibin Lv ◽

Ray T. Y. So ◽

Meng Yuan ◽

Hejun Liu ◽

Chang-Chun D. Lee ◽

...

Keyword(s):

Antibody Response ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Vaccination Strategy ◽

Vaccine Effectiveness ◽

Major Focus ◽

The World ◽

The One ◽

The Impact

SUMMARYAntigenic imprinting, which describes the bias of antibody response due to previous immune history, can influence vaccine effectiveness and has been reported in different viruses. Give that COVID-19 vaccine development is currently a major focus of the world, there is a lack of understanding of how background immunity influence antibody response to SARS-CoV-2. This study provides evidence for antigenic imprinting in Sarbecovirus, which is the subgenus that SARS-CoV-2 belongs to. Specifically, we sequentially immunized mice with two antigenically distinct Sarbecovirus strains, namely SARS-CoV and SARS-CoV-2. We found that the neutralizing antibodies triggered by the sequentially immunization are dominantly against the one that is used for priming. Given that the impact of the background immunity on COVID-19 is still unclear, our results will provide important insights into the pathogenesis of this disease as well as COVID-19 vaccination strategy.

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Immunogenicity and Cross-Reactivity of Rhesus Adenoviral Vectors

Journal of Virology ◽

10.1128/jvi.00159-18 ◽

2018 ◽

Vol 92 (11) ◽

Cited By ~ 2

Author(s):

M. Justin Iampietro ◽

Rafael A. Larocca ◽

Nicholas M. Provine ◽

Peter Abbink ◽

Zi Han Kang ◽

...

Keyword(s):

T Cell ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

T Cell Responses ◽

Adenoviral Vectors ◽

Cross Reactivity ◽

Human Populations ◽

Humoral Immune ◽

Cell Responses ◽

The Impact

ABSTRACT Adenovirus (Ad) vectors are being investigated as vaccine candidates, but baseline antivector immunity exists in human populations to both human Ad (HuAd) and chimpanzee Ad (ChAd) vectors. In this study, we investigated the immunogenicity and cross-reactivity of a panel of recently described rhesus adenoviral (RhAd) vectors. RhAd vectors elicited T cells with low exhaustion markers and robust anamnestic potential. Moreover, RhAd vector immunogenicity was unaffected by high levels of preexisting anti-HuAd immunity. Both HuAd/RhAd and RhAd/RhAd prime-boost vaccine regimens were highly immunogenic, despite a degree of cross-reactive neutralizing antibodies (NAbs) between phylogenetically related RhAd vectors. We observed extensive vector-specific cross-reactive CD4 T cell responses and more limited CD8 T cell responses between RhAd and HuAd vectors, but the impact of vector-specific cellular responses was far less than that of vector-specific NAbs. These data suggest the potential utility of RhAd vectors and define novel heterologous prime-boost strategies for vaccine development. IMPORTANCE To date, most adenoviral vectors developed for vaccination have been HuAds from species B, C, D, and E, and human populations display moderate to high levels of preexisting immunity. There is a clinical need for new adenoviral vectors that are not hindered by preexisting immunity. Moreover, the development of RhAd vector vaccines expands our ability to vaccinate against multiple pathogens in a population that may have received other HuAd or ChAd vectors. We evaluated the immunogenicity and cross-reactivity of RhAd vectors, which belong to the poorly described adenovirus species G. These vectors induced robust cellular and humoral immune responses and were not hampered by preexisting anti-HuAd vector immunity. Such properties make RhAd vectors attractive as potential vaccine vectors.

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Immunogenicity and safety of an inactivated virus vaccine against SARS-CoV-2 in patients with autoimmune rheumatic diseases

10.21203/rs.3.rs-551982/v1 ◽

2021 ◽

Author(s):

Eloisa Bonfa ◽

Ana Medeiros-Ribeiro ◽

Nadia Aikawa ◽

Carla Saad ◽

Emily Yuki ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Matched Control ◽

Controlled Study ◽

Control Group ◽

Neutralization Activity ◽

Autoimmune Rheumatic Diseases ◽

Excellent Safety Profile ◽

The Impact ◽

Prospective Controlled Study ◽

Dose Vaccine

Abstract CoronaVac(SARS-CoV-2 inactivated vaccine) has been largely used as the main immunogen for COVID-19 in several countries. However, its immunogenicity in immunocompromised individuals has not been established. This was a prospective controlled study of 910 adult ARD patients and 182 age- and sex-matched control group(CG) who received two doses of CoronaVac in a 28-days interrval. Anti-SARS-Cov-2 IgG and neutralizing antibodies were assessed at each vaccine shot and 6 weeks after the 2nd dose. Vaccine adverse events(AE) were similar in both groups. We observed significant lower anti-SARS-Cov-2 IgG seroconversion(70.4% vs. 95.5%,p < 0.001) and titers[12.1(95%CI 11.0-13.2) vs. 29.7(95%CI 26.3–33.5),p < 0.001], frequency of neutralizing antibodies(56.3% vs. 79.3%),p < 0.001) and median (interquartile range) neutralization activity [58.7(43.1–77.2) vs. 64.5(48.4–81.4),p = 0.013] in ARD patients compared to CG. A significant decline in the number of COVID-19 cases (p < 0.0001) were observed 10 days after the second dose, with a predominant P1 variant. Safety analysis revealed no moderate/severe AEs. In conclusion, CoronaVac has an excellent safety profile and reasonable rates of quantitative serology(70.4%)/neutralization(56.3%) in ARD patients. The impact of this reduced immunogenicity in vaccine effectiveness warrants further evaluation.

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Immunogenicity of heterologous BNT162b2 booster in fully vaccinated individuals with CoronaVac against SARS-CoV-2 variants Delta and Omicron: the Dominican Republic Experience

10.1101/2021.12.27.21268459 ◽

2021 ◽

Author(s):

Eddy Perez-Then ◽

Carolina Lucas ◽

Valter Silva Monteiro ◽

Marija Miric ◽

Vivian Brache ◽

...

Keyword(s):

Dominican Republic ◽

Dose Regimen ◽

Neutralizing Antibodies ◽

Immune Escape ◽

Neutralizing Antibody ◽

Fold Increase ◽

Neutralization Activity ◽

Recent Emergence ◽

Virus Specific Antibody ◽

The Impact

The recent emergence of the SARS-CoV-2 Omicron variant is raising concerns because of its increased transmissibility and by its numerous spike mutations with potential to evade neutralizing antibodies elicited by COVID-19 vaccines. The Dominican Republic was among the first countries in recommending the administration of a third dose COVID-19 vaccine to address potential waning immunity and reduced effectiveness against variants. Here, we evaluated the effects of a heterologous BNT162b2 mRNA vaccine booster on the humoral immunity of participants that had received a two-dose regimen of CoronaVac, an inactivated vaccine used globally. We found that heterologous CoronaVac prime followed by BNT162b2 booster regimen induces elevated virus-specific antibody levels and potent neutralization activity against the ancestral virus and Delta variant, resembling the titers obtained after two doses of mRNA vaccines. While neutralization of Omicron was undetectable in participants that had received a two-dose regimen of CoronaVac vaccine, BNT162b2 booster resulted in a 1.4-fold increase in neutralization activity against Omicron, compared to two-dose mRNA vaccine. Despite this increase, neutralizing antibody titers were reduced by 6.3-fold and 2.7-fold for Omicron compared to ancestral and Delta variant, respectively. Surprisingly, previous SARS-CoV-2 infection did not affect the neutralizing titers for Omicron in participants that received the heterologous regimen. Our findings have immediate implications for multiples countries that previously used a two-dose regimen of CoronaVac and reinforce the notion that the Omicron variant is associated with immune escape from vaccines or infection-induced immunity, highlighting the global need for vaccine boosters to combat the impact of emerging variants.

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Overlapping Impacts of HIV/COVID-19 Pandemic on HIV Vaccine Development

10.47363/jvrr/2020(1)115 ◽

2020 ◽

pp. 1-7

Author(s):

Seyi Samson Enitan ◽

◽

Surajudeen Alim Junaid ◽

Richard Yomi Akele ◽

◽

...

Keyword(s):

Neutralizing Antibodies ◽

Ethical Issues ◽

Vaccine Development ◽

Stringent Response ◽

Rapid Test ◽

Vaccine Safety ◽

Hiv Vaccine ◽

Potential Exposure ◽

Clinic Staff ◽

The Impact

The quest for a safe and effective HIV vaccine holds life-saving potential for people globally. Interestingly, the HIV/COVID-19 overlapping pandemic have impacted each other in diverse ways, some being advantageous, while others detrimental. On one hand, the HIV platforms for development of rapid test kits, neutralizing antibodies, vaccine development and trials, collaboration and mobilization etc. has proved very helpful and a promising template for the development of interventions for the COVID-19 pandemic; while on the other hand, a number of ongoing HIV vaccine safety and efficacy trials are being abridged, stopped or suspended amidst the Coronavirus Disease-19 (COVID-19) crisis. The COVID-19 outbreak that begun in Wuhan, megacity of China late December, 2019, has spread to 220 countries and territories, with more than 36 million total confirmed cases and 1,057,505 total deaths globally as at 08 October, 2020 and still counting. Currently, no approved vaccines exist to prevent infection with the novel Coronavirus, however, the impact of the pandemic has been enormous with devastating effects on the global health and economy, with many countries introducing stringent response measures to de-escalate the spread of the virus. Recruiting and retaining volunteers for HIV vaccine trials this period has become very challenging due to a lot of factors including fear of potential exposure to the new coronavirus, ethical issues and safety concerns amongst others. The protection and safety of participants and clinic staff remain a priority for HIV vaccine investigators worldwide. They are at the moment making conscious efforts to execute measures necessary to prevent potential exposure and transmission of COVID-19 among study participants and clinic staff in various study sites. This review takes a look at the overlapping impacts of the HIV/COVID-19 pandemic on HIV vaccine development.

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Functional mapping of B-cell linear epitopes of SARS-CoV-2 in COVID-19 convalescent population

10.1101/2020.07.25.20161869 ◽

2020 ◽

Author(s):

Zhigang Yi ◽

Yun Ling ◽

Xiaonan Zhang ◽

Jieliang Chen ◽

Kongying Hu ◽

...

Keyword(s):

Viral Infection ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Neutralization Assay ◽

Receptor Binding Domain ◽

E Proteins ◽

Neutralization Activity ◽

Vaccine Candidates ◽

Linear Epitopes ◽

Specific Antigens

Pandemic SARS-CoV-2 has infected over 10 million people and caused over 500,000 mortalities. Vaccine development is in urgent need to stop the pandemic. Despite great progresses on SARS-CoV-2 vaccine development, the efficacy of the vaccines remains to be determined. Deciphering the interactions of the viral epitopes with their elicited neutralizing antibodies in the convalescent COVID-19 population inspires the vaccine development. In this study, we devised a peptide array composed of 20-mer overlapped peptides of spike (S), membrane (M) and envelope (E) proteins, and performed a screening with 120 COVID-19 convalescent serums and 24 non-COVID-19 serums. We identified five SARS-CoV-2-specific dominant epitopes that reacted with above 40% COVID-19 convalescent serums. Epitopes in the receptor-binding domain (RBD) of S ill reacted with the convalescent serums. Of note, two peptides non-specifically interacted with most of the non-COVID-19 serums. Neutralization assay indicated that only five serums completely blocked viral infection at the dilution of 1:200. By using a peptide-compete neutralizing assay, we found that three dominant epitopes partially competed the neutralization activity of several convalescent serums, suggesting antibodies elicited by these epitopes played an important role in neutralizing viral infection. The epitopes we identified in this study may serve as vaccine candidates to elicit neutralizing antibodies in most vaccinated people or specific antigens for SARS-CoV-2 diagnosis.

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Immunization of Rabbits with Recombinant Human Cytomegalovirus Trimeric versus Monomeric gH/gL Protein Elicits Markedly Higher Titers of Antibody and Neutralization Activity

International Journal of Molecular Sciences ◽

10.3390/ijms20133158 ◽

2019 ◽

Vol 20 (13) ◽

pp. 3158 ◽

Cited By ~ 3

Author(s):

Xinle Cui ◽

Zhouhong Cao ◽

Shuishu Wang ◽

Michael Flora ◽

Stuart P. Adler ◽

...

Keyword(s):

Human Cytomegalovirus ◽

Neutralizing Antibodies ◽

Hcmv Infection ◽

Vaccine Development ◽

Vaccine Candidate ◽

Host Cells ◽

Neutralization Activity ◽

Neutralizing Activity ◽

Immunosuppressed Patients ◽

Specific Igg

Congenital human cytomegalovirus (HCMV) infection and HCMV infection of immunosuppressed patients cause significant morbidity and mortality, and vaccine development against HCMV is a major public health priority. HCMV envelope glycoproteins gB, gH, and gL, which constitute the core fusion machinery, play critical roles in HCMV fusion and entry into host cells. HCMV gB and gH/gL have been reported to elicit potent neutralizing antibodies. Recently, the gB/gH/gL complex was identified in the envelope of HCMV virions, and 16–50% of the total gH/gL bound to gB, forming the gB/gH/gL complex. These findings make the gB/gH/gL a unique HCMV vaccine candidate. We previously reported the production of HCMV trimeric gB and gH/gL heterodimers, and immunization with a combination of trimeric gB and gH/gL heterodimers elicited strong synergistic HCMV-neutralizing activity. To further improve the immunogenicity of gH/gL, we produced trimeric gH/gL. Rabbits immunized with HCMV trimeric gH/gL induced up to 38-fold higher serum titers of gH/gL-specific IgG relative to HCMV monomeric gH/gL, and elicited ~10-fold higher titers of complement-dependent and complement-independent HCMV-neutralizing activity for both epithelial cells and fibroblasts. HCMV trimeric gH/gL in combination with HCMV trimeric gB would be a novel promising HCMV vaccine candidate that could induce highly potent neutralizing activities.

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Genetic engineering applied to the development of vaccines

Philosophical Transactions of the Royal Society of London Series B Biological Sciences ◽

10.1098/rstb.1989.0060 ◽

1989 ◽

Vol 324 (1224) ◽

pp. 461-476

Keyword(s):

Genetic Engineering ◽

Neutralizing Antibodies ◽

Antigenic Variation ◽

Vaccine Development ◽

Genetic Manipulation ◽

Immunological Response ◽

Core Antigen ◽

B Virus ◽

The Impact

The simplest application of the modern genetic manipulation methods to vaccine development is the expression in microbial cells of genes from pathogens that encode surface antigens capable of inducing neutralizing antibodies in the host of the pathogen involved. This procedure has been exploited successfully for development of a vaccine against hepatitis B virus (hbv) that is now widely used. Similar approaches have been directed towards formulations for immunization against several other animal and human diseases and some of these preparations are now presently in trials. Of no less importance is the impact of biotechnology in providing reagents for fundamental studies of topics such as the determination of virulence, antigenic variation, virus receptors and the immunological response to viral antigens. The core antigen of hbv is a good example of a product of genetic engineering that is a valuable diagnostic reagent, and that is finding important use in immunological studies of particular pertinence to vaccine development.

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Interests of the Non-Human Primate Models for HIV Cure Research

Vaccines ◽

10.3390/vaccines9090958 ◽

2021 ◽

Vol 9 (9) ◽

pp. 958

Author(s):

Gauthier Terrade ◽

Nicolas Huot ◽

Caroline Petitdemange ◽

Marie Lazzerini ◽

Aurelio Orta Resendiz ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Vaccine Development ◽

Envelope Gene ◽

Hiv Cure ◽

Viral Reservoirs ◽

Immunodeficiency Virus ◽

Hiv Cure Research ◽

Hiv Envelope ◽

The Impact ◽

Human Primate

Non-human primate (NHP) models are important for vaccine development and also contribute to HIV cure research. Although none of the animal models are perfect, NHPs enable the exploration of important questions about tissue viral reservoirs and the development of intervention strategies. In this review, we describe recent advances in the use of these models for HIV cure research and highlight the progress that has been made as well as limitations using these models. The main NHP models used are (i) the macaque, in which simian immunodeficiency virus (SIVmac) infection displays similar replication profiles as to HIV in humans, and (ii) the macaque infected by a recombinant virus (SHIV) consisting of SIVmac expressing the HIV envelope gene serving for studies analyzing the impact of anti-HIV Env broadly neutralizing antibodies. Lessons for HIV cure that can be learned from studying the natural host of SIV are also presented here. An overview of the most promising and less well explored HIV cure strategies tested in NHP models will be given.

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Role of the E2 Hypervariable Region (HVR1) in the Immunogenicity of a Recombinant Hepatitis C Virus Vaccine

Journal of Virology ◽

10.1128/jvi.02141-17 ◽

2018 ◽

Vol 92 (11) ◽

Cited By ~ 13

Author(s):

John L. M. Law ◽

Michael Logan ◽

Jason Wong ◽

Juthika Kundu ◽

Darren Hockman ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Neutralizing Antibodies ◽

Hypervariable Region ◽

Vaccine Antigen ◽

Current Evidence ◽

Pseudotyped Virus ◽

Wild Type ◽

Neutralization Activity ◽

Neutralizing Epitopes

ABSTRACTCurrent evidence supports a protective role for virus-neutralizing antibodies in immunity against hepatitis C virus (HCV) infection. Many cross-neutralizing monoclonal antibodies have been identified. These antibodies have been shown to provide protection or to clear infection in animal models. Previous clinical trials have shown that a gpE1/gpE2 vaccine can induce antibodies that neutralize thein vitroinfectivity of all the major cell culture-derived HCV (HCVcc) genotypes around the world. However, cross-neutralization appeared to favor certain genotypes, with significant but lower neutralization against others. HCV may employ epitope masking to avoid antibody-mediated neutralization. Hypervariable region 1 (HVR1) at the amino terminus of glycoprotein E2 has been shown to restrict access to many neutralizing antibodies. Consistent with this, other groups have reported that recombinant viruses lacking HVR1 are hypersensitive to neutralization. It has been proposed that gpE1/gpE2 lacking this domain could be a better vaccine antigen to induce broadly neutralizing antibodies. In this study, we examined the immunogenicity of recombinant gpE1/gpE2 lacking HVR1 (ΔHVR1). Our results indicate that wild-type (WT) and ΔHVR1 gpE1/gpE2 antigens induced antibodies targeting many well-characterized cross-genotype-neutralizing epitopes. However, while the WT gpE1/gpE2 vaccine can induce cross-genotype protection against various genotypes of HCVcc and/or HCV-pseudotyped virus (HCVpp), antisera from ΔHVR1 gpE1/gpE2-immunized animals exhibited either reduced homologous neutralization activity compared to that of the WT or heterologous neutralization activity similar to that of the WT. These data suggest that ΔHVR1 gpE1/gpE2 is not a superior vaccine antigen. Based on previously reported chimpanzee protection data using WT gpE1/gpE2 and our current findings, we are preparing a combination vaccine including wild-type recombinant gpE1/gpE2 for clinical testing in the future.IMPORTANCEAn HCV vaccine is an unmet medical need. Current evidence suggests that neutralizing antibodies play an important role in virus clearance, along with cellular immune responses. Previous clinical data showed that gpE1/gpE2 can effectively induce cross-neutralizing antibodies, although they favor certain genotypes. HCV employs HVR1 within gpE2 to evade host immune control. It has been hypothesized that the removal of this domain would improve the production of cross-neutralizing antibodies. In this study, we compared the immunogenicities of WT and ΔHVR1 gpE1/gpE2 antigens as vaccine candidates. Our results indicate that the ΔHVR1 gpE1/gpE2 antigen confers no advantages in the neutralization of HCV compared with the WT antigen. Previously, we showed that this WT antigen remains the only vaccine candidate to protect chimpanzees from chronic infection, contains multiple cross-neutralizing epitopes, and is well tolerated and immunogenic in humans. The current data support the further clinical development of this vaccine antigen component.

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