scholarly journals MVA vector expression of SARS-CoV-2 spike protein and protection of adult Syrian hamsters against SARS-CoV-2 challenge

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Clement A. Meseda ◽  
Charles B. Stauft ◽  
Prabhuanand Selvaraj ◽  
Christopher Z. Lien ◽  
Cyntia Pedro ◽  
...  
Keyword(s):  
Vaccine Development ◽  
Protective Efficacy ◽  
Neutralizing Antibody ◽  
Virus Shedding ◽  
Vaccine Candidates ◽  
Syrian Hamsters ◽  
Modified Vaccinia Virus Ankara ◽  
Dose Ranging ◽  
Subcutaneous Immunization

AbstractNumerous vaccine candidates against SARS-CoV-2, the causative agent of the COVID-19 pandemic, are under development. The majority of vaccine candidates to date are designed to induce immune responses against the viral spike (S) protein, although different forms of S antigen have been incorporated. To evaluate the yield and immunogenicity of different forms of S, we constructed modified vaccinia virus Ankara (MVA) vectors expressing full-length S (MVA-S), the RBD, and soluble S ectodomain and tested their immunogenicity in dose-ranging studies in mice. All three MVA vectors induced spike-specific immunoglobulin G after one subcutaneous immunization and serum titers were boosted following a second immunization. The MVA-S and MVA-ssM elicited the strongest neutralizing antibody responses. In assessing protective efficacy, MVA-S-immunized adult Syrian hamsters were challenged with SARS-CoV-2 (USA/WA1/2020). MVA-S-vaccinated hamsters exhibited less severe manifestations of atypical pneumocyte hyperplasia, hemorrhage, vasculitis, and especially consolidation, compared to control animals. They also displayed significant reductions in gross pathology scores and weight loss, and a moderate reduction in virus shedding was observed post challenge in nasal washes. There was evidence of reduced viral replication by in situ hybridization, although the reduction in viral RNA levels in lungs and nasal turbinates did not reach significance. Taken together, the data indicate that immunization with two doses of an MVA vector expressing SARS-CoV-2 S provides protection against a stringent SARS-CoV-2 challenge of adult Syrian hamsters, reaffirm the utility of this animal model for evaluating candidate SARS-CoV-2 vaccines, and demonstrate the value of an MVA platform in facilitating vaccine development against SARS-CoV-2.

Broad neutralization of H1 and H3 viruses by adjuvanted influenza HA stem vaccines in nonhuman primates

2021 ◽  
Vol 13 (583) ◽  
pp. eabe5449
Author(s):  
Nicole Darricarrère ◽  
Yu Qiu ◽  
Masaru Kanekiyo ◽  
Adrian Creanga ◽  
Rebecca A. Gillespie ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Nonhuman Primates ◽  
Vaccine Development ◽  
Protective Efficacy ◽  
Neutralizing Antibody ◽  
Gene Families ◽  
Influenza Viruses ◽  
Public Health Importance ◽  
Water Emulsion

Seasonal influenza vaccines confer protection against specific viral strains but have restricted breadth that limits their protective efficacy. The H1 and H3 subtypes of influenza A virus cause most of the seasonal epidemics observed in humans and are the major drivers of influenza A virus–associated mortality. The consequences of pandemic spread of COVID-19 underscore the public health importance of prospective vaccine development. Here, we show that headless hemagglutinin (HA) stabilized-stem immunogens presented on ferritin nanoparticles elicit broadly neutralizing antibody (bnAb) responses to diverse H1 and H3 viruses in nonhuman primates (NHPs) when delivered with a squalene-based oil-in-water emulsion adjuvant, AF03. The neutralization potency and breadth of antibodies isolated from NHPs were comparable to human bnAbs and extended to mismatched heterosubtypic influenza viruses. Although NHPs lack the immunoglobulin germline VH1-69 residues associated with the most prevalent human stem-directed bnAbs, other gene families compensated to generate bnAbs. Isolation and structural analyses of vaccine-induced bnAbs revealed extensive interaction with the fusion peptide on the HA stem, which is essential for viral entry. Antibodies elicited by these headless HA stabilized-stem vaccines neutralized diverse H1 and H3 influenza viruses and shared a mode of recognition analogous to human bnAbs, suggesting that these vaccines have the potential to confer broadly protective immunity against diverse viruses responsible for seasonal and pandemic influenza infections in humans.

scholarly journals Protective efficacy of rhesus adenovirus COVID-19 vaccines against mouse-adapted SARS-CoV-2

2021 ◽  
Author(s):  
Lisa H. Tostanoski ◽  
Lisa E. Gralinski ◽  
David R. Martinez ◽  
Alexandra Schaefer ◽  
Shant H. Mahrokhian ◽  
...  
Keyword(s):  
Viral Replication ◽  
Protective Efficacy ◽  
Neutralizing Antibody ◽  
Wild Type ◽  
Adenovirus Serotype ◽  
Vaccine Candidates ◽  
Correlates Of Protection ◽  
Immune Correlates ◽  
Antibody Titers ◽  
Adenovirus Vectors

The global COVID-19 pandemic has sparked intense interest in the rapid development of vaccines as well as animal models to evaluate vaccine candidates and to define immune correlates of protection. We recently reported a mouse-adapted SARS-CoV-2 virus strain (MA10) with the potential to infect wild-type laboratory mice, driving high levels of viral replication in respiratory tract tissues as well as severe clinical and respiratory symptoms, aspects of COVID-19 disease in humans that are important to capture in model systems. We evaluated the immunogenicity and protective efficacy of novel rhesus adenovirus serotype 52 (RhAd52) vaccines against MA10 challenge in mice. Baseline seroprevalence is lower for rhesus adenovirus vectors than for human or chimpanzee adenovirus vectors, making these vectors attractive candidates for vaccine development. We observed that RhAd52 vaccines elicited robust binding and neutralizing antibody titers, which inversely correlated with viral replication after challenge. These data support the development of RhAd52 vaccines and the use of the MA10 challenge virus to screen novel vaccine candidates and to study the immunologic mechanisms that underscore protection from SARS-CoV-2 challenge in wild-type mice. Importance We have developed a series of SARS-CoV-2 vaccines using rhesus adenovirus serotype 52 (RhAd52) vectors, which exhibits a lower seroprevalence than human and chimpanzee vectors, supporting their development as novel vaccine vectors or as an alternative Ad vector for boosting. We sought to test these vaccines using a recently reported mouse-adapted SARS-CoV-2 (MA10) virus to i) evaluate the protective efficacy of RhAd52 vaccines and ii) further characterize this mouse-adapted challenge model and probe immune correlates of protection. We demonstrate RhAd52 vaccines elicit robust SARS-CoV-2-specific antibody responses and protect against clinical disease and viral replication in the lungs. Further, binding and neutralizing antibody titers correlated with protective efficacy. These data validate the MA10 mouse model as a useful tool to screen and study novel vaccine candidates, as well as the development of RhAd52 vaccines for COVID-19.

scholarly journals Global distribution of single amino acid polymorphisms in Plasmodium vivax Duffy-binding-like domain and implications for vaccine development efforts

Open Biology ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 200180
Author(s):  
Payal Mittal ◽  
Siddhartha Mishra ◽  
Sonalika Kar ◽  
Veena Pande ◽  
Abhinav Sinha ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Binding Sites ◽  
Vaccine Development ◽  
Vaccine Candidate ◽  
Neutralizing Antibody ◽  
Single Amino Acid ◽  
Vaccine Candidates ◽  
Malaria Burden ◽  
Single Amino Acid Polymorphisms ◽  
Polymorphic Residue

Plasmodium vivax ( Pv ) malaria continues to be geographically widespread with approximately 15 million worldwide cases annually. Along with other proteins, Duffy-binding proteins (DBPs) are used by plasmodium for RBC invasion and the parasite-encoded receptor binding regions lie in their Duffy-binding-like (DBL) domains—thus making it a prime vaccine candidate. This study explores the sequence diversity in Pv DBL globally, with an emphasis on India as it remains a major contributor to the global Pv malaria burden. Based on 1358 Pv DBL protein sequences available in NCBI, we identified 140 polymorphic sites within 315 residues of Pv DBL. Alarmingly, country-wise mapping of SAAPs from field isolates revealed varied and distinct polymorphic profiles for different nations. We report here 31 polymorphic residue positions in the global SAAP profile, most of which map to the Pv DBL subdomain 2 ( α 1– α 6). A distinct clustering of SAAPs distal to the DARC-binding sites is indicative of immune evasive strategies by the parasite. Analyses of Pv DBL-neutralizing antibody complexes revealed that between 24% and 54% of interface residues are polymorphic. This work provides a framework to recce and expand the polymorphic space coverage in Pv DBLs as this has direct implications for vaccine development studies. It also emphasizes the significance of surveying global SAAP distributions before or alongside the identification of vaccine candidates.

scholarly journals Modified Vaccinia Virus Ankara as a Viral Vector for Vaccine Candidates against Chikungunya Virus

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1122
Author(s):  
Juan García-Arriaza ◽  
Mariano Esteban ◽  
Daniel López
Keyword(s):  
Vaccinia Virus ◽  
Chikungunya Virus ◽  
Vaccine Development ◽  
Viral Vector ◽  
Severe Disease ◽  
Febrile Illness ◽  
Structural Proteins ◽  
Effective Vaccine ◽  
Vaccine Candidates ◽  
Modified Vaccinia Virus Ankara

There is a need to develop a highly effective vaccine against the emerging chikungunya virus (CHIKV), a mosquito-borne Alphavirus that causes severe disease in humans consisting of acute febrile illness, followed by chronic debilitating polyarthralgia and polyarthritis. In this review, we provide a brief history of the development of the first poxvirus vaccines that led to smallpox eradication and its implications for further vaccine development. As an example, we summarize the development of vaccine candidates based on the modified vaccinia virus Ankara (MVA) vector expressing different CHIKV structural proteins, paying special attention to MVA-CHIKV expressing all of the CHIKV structural proteins: C, E3, E2, 6K and E1. We review the characterization of innate and adaptive immune responses induced in mice and nonhuman primates by the MVA-CHIKV vaccine candidate and examine its efficacy in animal models, with promising preclinical findings needed prior to the approval of human clinical trials.

scholarly journals Parenterally Administered P24-VP8* Nanoparticle Vaccine Conferred Strong Protection against Rotavirus Diarrhea and Virus Shedding in Gnotobiotic Pigs

Vaccines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 177 ◽  
Author(s):  
Ramesh ◽  
Mao ◽  
Lei ◽  
Twitchell ◽  
Shiraz ◽  
...  
Keyword(s):  
Protective Efficacy ◽  
Neutralizing Antibody ◽  
T Cell Response ◽  
Antibody Responses ◽  
Post Inoculation ◽  
Virus Shedding ◽  
Diarrhea Virus ◽  
Rotavirus Vaccines ◽  
Increased Risk ◽  
Rotavirus Diarrhea

Current live rotavirus vaccines are costly with increased risk of intussusception due to vaccine replication in the gut of vaccinated children. New vaccines with improved safety and cost-effectiveness are needed. In this study, we assessed the immunogenicity and protective efficacy of a novel P24-VP8* nanoparticle vaccine using the gnotobiotic (Gn) pig model of human rotavirus infection and disease. Three doses of P24-VP8* (200 μg/dose) intramuscular vaccine with Al(OH)3 adjuvant (600 μg) conferred significant protection against infection and diarrhea after challenge with virulent Wa strain rotavirus. This was indicated by the significant reduction in the mean duration of diarrhea, virus shedding in feces, and significantly lower fecal cumulative consistency scores in post-challenge day (PCD) 1–7 among vaccinated pigs compared to the mock immunized controls. The P24-VP8* vaccine was highly immunogenic in Gn pigs. It induced strong VP8*-specific serum IgG and Wa-specific virus-neutralizing antibody responses from post-inoculation day 21 to PCD 7, but did not induce serum or intestinal IgA antibody responses or a strong effector T cell response, which are consistent with the immunization route, the adjuvant used, and the nature of the non-replicating vaccine. The findings are highly translatable and thus will facilitate clinical trials of the P24-VP8* nanoparticle vaccine.

scholarly journals Immunogenicity and protective efficacy of inactivated SARS-CoV-2 vaccine candidate, BBV152 in rhesus macaques

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Pragya D. Yadav ◽  
Raches Ella ◽  
Sanjay Kumar ◽  
Dilip R. Patil ◽  
Sreelekshmy Mohandas ◽  
...  
Keyword(s):  
Vaccine Candidate ◽  
Histopathological Examination ◽  
Protective Efficacy ◽  
Rhesus Macaques ◽  
Alveolar Epithelium ◽  
Neutralizing Antibody ◽  
Lavage Fluid ◽  
Phase Iii ◽  
Health Crisis ◽  
Vaccine Candidates

AbstractThe COVID-19 pandemic is a global health crisis that poses a great challenge to the public health system of affected countries. Safe and effective vaccines are needed to overcome this crisis. Here, we develop and assess the protective efficacy and immunogenicity of an inactivated SARS-CoV-2 vaccine in rhesus macaques. Twenty macaques were divided into four groups of five animals each. One group was administered a placebo, while three groups were immunized with three different vaccine candidates of BBV152 at 0 and 14 days. All the macaques were challenged with SARS-CoV-2 fourteen days after the second dose. The protective response was observed with increasing SARS-CoV-2 specific IgG and neutralizing antibody titers from 3rd-week post-immunization. Viral clearance was observed from bronchoalveolar lavage fluid, nasal swab, throat swab and lung tissues at 7 days post-infection in the vaccinated groups. No evidence of pneumonia was observed by histopathological examination in vaccinated groups, unlike the placebo group which exhibited interstitial pneumonia and localization of viral antigen in the alveolar epithelium and macrophages by immunohistochemistry. This vaccine candidate BBV152 has completed Phase I/II (NCT04471519) clinical trials in India and is presently in phase III, data of this study substantiates the immunogenicity and protective efficacy of the vaccine candidates.

scholarly journals Protective Efficacy and Immunogenicity of an Adenoviral Vector Vaccine Encoding the Codon-Optimized F Protein of Respiratory Syncytial Virus

2009 ◽  
Vol 83 (23) ◽  
pp. 12601-12610 ◽  
Author(s):  
Rebekka Kohlmann ◽  
Sarah Schwannecke ◽  
Bettina Tippler ◽  
Nicola Ternette ◽  
Vladimir V. Temchura ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Vaccine Development ◽  
Protective Efficacy ◽  
Neutralizing Antibody ◽  
Soluble Form ◽  
Booster Immunization ◽  
Vector Vaccine ◽  
F Gene ◽  
Viral Loads ◽  
Syncytial Virus

ABSTRACT Adenoviral vectors (AdV) have received considerable attention for vaccine development because of their high immunogenicity and efficacy. In previous studies, it was shown that DNA immunization of mice with codon-optimized expression plasmids encoding the fusion protein of respiratory syncytial virus (RSV F) resulted in enhanced protection against RSV challenge compared to immunization with plasmids carrying the wild-type cDNA sequence of RSV F. In this study, we constructed AdV carrying the codon-optimized full-length RSV F gene (AdV-F) or the soluble form of the RSV F gene (AdV-Fsol). BALB/c mice were immunized twice with AdV-F or AdV-Fsol and challenged with RSV intranasally. Substantial levels of antibody to RSV F were induced by both AdV vaccines, with peak neutralizing-antibody titers of 1:900. Consistently, the viral loads in lung homogenates and bronchoalveolar lavage fluids were significantly reduced by a factor of more than 60,000. The protection against viral challenge could be measured even 8 months after the booster immunization. AdV-F and AdV-Fsol induced similar levels of immunogenicity and protective efficacy. Therefore, these results encourage further development of AdV vaccines against RSV infection in humans.

scholarly journals Protective efficacy of rhesus adenovirus COVID-19 vaccines against mouse-adapted SARS-CoV-2

2021 ◽  
Author(s):  
Lisa Tostanoski ◽  
Lisa Gralinski ◽  
David Martinez ◽  
Alexandra Schaefer ◽  
Shant Mahrokhian ◽  
...  
Keyword(s):  
Viral Replication ◽  
Vaccine Development ◽  
Protective Efficacy ◽  
Rapid Development ◽  
Model Systems ◽  
Wild Type ◽  
Challenge Virus ◽  
Vaccine Candidates ◽  
Immune Correlates ◽  
Adenovirus Vectors

The global COVID-19 pandemic has sparked intense interest in the rapid development of vaccines as well as animal models to evaluate vaccine candidates and to define immune correlates of protection. We recently reported a mouse-adapted SARS-CoV-2 virus strain (MA10) with the potential to infect wild-type laboratory mice, driving high levels of viral replication in respiratory tract tissues as well as severe clinical and respiratory symptoms, aspects of COVID-19 disease in humans that are important to capture in model systems. We evaluated the immunogenicity and protective efficacy of novel rhesus adenovirus serotype 52 (RhAd52) vaccines against MA10 challenge in mice. Baseline seroprevalence is lower for rhesus adenovirus vectors than for human or chimpanzee adenovirus vectors, making these vectors attractive candidates for vaccine development. We observed that RhAd52 vaccines elicited robust binding and neutralizing antibody titers, which inversely correlated with viral replication after challenge. These data support the development of RhAd52 vaccines and the use of the MA10 challenge virus to screen novel vaccine candidates and to study the immunologic mechanisms that underscore protection from SARS-CoV-2 challenge in wild-type mice.

scholarly journals Remarkable immunogenicity and protective efficacy of BBV152, an inactivated SARS-CoV-2 vaccine in rhesus macaques

2020 ◽  
Author(s):  
Pragya Yadav ◽  
Raches Ella ◽  
Sanjay Kumar ◽  
Dilip Patil ◽  
Sreelekshmy Mohandas ◽  
...  
Keyword(s):  
Histopathological Examination ◽  
Protective Efficacy ◽  
Rhesus Macaques ◽  
Alveolar Epithelium ◽  
Neutralizing Antibody ◽  
Lavage Fluid ◽  
Effective Vaccine ◽  
Phase I Clinical Trials ◽  
Health Crisis ◽  
Vaccine Candidates

Abstract The COVID-19 pandemic is a global health crisis that has severely affected mankind and posed a great challenge to the public health system of affected countries. The availability of a safe and effective vaccine is the need of the hour to overcome this crisis. Here, we have developed and assessed the protective efficacy and immunogenicity of an inactivated SARS-CoV-2 vaccine (BBV152) in rhesus macaques (Macaca mulata). Twenty macaques were divided into four groups of five animals each. One group was administered a placebo while three groups were immunized with three different vaccine candidates at 0 and 14 days. All the macaques were challenged with SARS-CoV-2 fourteen days after the second dose. The protective response was observed with increasing SARS-CoV-2 specific IgG and neutralizing antibody titers from 3rd-week post-immunization. Viral clearance was observed from bronchoalveolar lavage fluid, nasal swab, throat swab, and lung tissues at 7 days post-infection in the vaccinated groups. No evidence of pneumonia was observed by histopathological examination in vaccinated groups, unlike the placebo group which showed features of interstitial pneumonia and localization of viral antigen in the alveolar epithelium and macrophages by immunohistochemistry. Data from this study substantiate the immunogenicity of the vaccine candidates and BBV152 is being evaluated in Phase I clinical trials in India (NCT04471519).

scholarly journals Rational Design of Toxoid Vaccine Candidates for Staphylococcus aureus Leukocidin AB (LukAB)

Toxins ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 339 ◽  
Author(s):  
Shweta Kailasan ◽  
Thomas Kort ◽  
Ipsita Mukherjee ◽  
Grant C. Liao ◽  
Tulasikumari Kanipakala ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Rational Design ◽  
Vaccine Development ◽  
Polyclonal Antibodies ◽  
Neutralizing Antibody ◽  
Mortality And Morbidity ◽  
Vaccine Candidates ◽  
Novel Approach ◽  
Antibody Titers ◽  
Opsonophagocytic Killing

Staphylococcus aureus (SA) infections cause high mortality and morbidity in humans. Being central to its pathogenesis, S. aureus thwarts the host defense by secreting a myriad of virulence factors, including bicomponent, pore-forming leukotoxins. While all vaccine development efforts that aimed at achieving opsonophagocytic killing have failed, targeting virulence by toxoid vaccines represents a novel approach to preventing mortality and morbidity that are caused by SA. The recently discovered leukotoxin LukAB kills human phagocytes and monocytes and it is present in all known S. aureus clinical isolates. While using a structure-guided approach, we generated a library of mutations that targeted functional domains within the LukAB heterodimer to identify attenuated toxoids as potential vaccine candidates. The mutants were evaluated based on expression, solubility, yield, biophysical properties, cytotoxicity, and immunogenicity, and several fully attenuated LukAB toxoids that were capable of eliciting high neutralizing antibody titers were identified. Rabbit polyclonal antibodies against the lead toxoid candidate provided potent neutralization of LukAB. While the neutralization of LukAB alone was not sufficient to fully suppress leukotoxicity in supernatants of S. aureus USA300 isolates, a combination of antibodies against LukAB, α-toxin, and Panton-Valentine leukocidin completely neutralized the cytotoxicity of these strains. These data strongly support the inclusion of LukAB toxoids in a multivalent toxoid vaccine for the prevention of S. aureus disease.

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