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

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.

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Progress and challenges in TB vaccine development

F1000Research ◽

10.12688/f1000research.13588.1 ◽

2018 ◽

Vol 7 ◽

pp. 199 ◽

Cited By ~ 51

Author(s):

Gerald Voss ◽

Danilo Casimiro ◽

Olivier Neyrolles ◽

Ann Williams ◽

Stefan H.E. Kaufmann ◽

...

Keyword(s):

Clinical Trials ◽

Vaccine Development ◽

Scientific Progress ◽

Human Infection ◽

Experimental Medicine ◽

Vaccine Platform ◽

Vaccine Candidates ◽

Clinical Endpoints ◽

Immune Correlates ◽

Efficacy Trials

The Bacille Calmette Guerin (BCG) vaccine can provide decades of protection against tuberculosis (TB) disease, and although imperfect, BCG is proof that vaccine mediated protection against TB is a possibility. A new TB vaccine is, therefore, an inevitability; the question is how long will it take us to get there? We have made substantial progress in the development of vaccine platforms, in the identification of antigens and of immune correlates of risk of TB disease. We have also standardized animal models to enable head-to-head comparison and selection of candidate TB vaccines for further development. To extend our understanding of the safety and immunogenicity of TB vaccines we have performed experimental medicine studies to explore route of administration and have begun to develop controlled human infection models. Driven by a desire to reduce the length and cost of human efficacy trials we have applied novel approaches to later stage clinical development, exploring alternative clinical endpoints to prevention of disease outcomes. Here, global leaders in TB vaccine development discuss the progress made and the challenges that remain. What emerges is that, despite scientific progress, few vaccine candidates have entered clinical trials in the last 5 years and few vaccines in clinical trials have progressed to efficacy trials. Crucially, we have undervalued the knowledge gained from our “failed” trials and fostered a culture of risk aversion that has limited new funding for clinical TB vaccine development. The unintended consequence of this abundance of caution is lack of diversity of new TB vaccine candidates and stagnation of the clinical pipeline. We have a variety of new vaccine platform technologies, mycobacterial antigens and animal and human models. However, we will not encourage progression of vaccine candidates into clinical trials unless we evaluate and embrace risk in pursuit of vaccine development.

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Development of an Aotus nancymaae Model for Shigella Vaccine Immunogenicity and Efficacy Studies

Infection and Immunity ◽

10.1128/iai.01665-13 ◽

2014 ◽

Vol 82 (5) ◽

pp. 2027-2036 ◽

Cited By ~ 6

Author(s):

Michael Gregory ◽

Robert W. Kaminski ◽

Luis A. Lugo-Roman ◽

Hugo Galvez Carrillo ◽

Drake Hamilton Tilley ◽

...

Keyword(s):

Vaccine Strain ◽

Attack Rate ◽

Vaccine Development ◽

Protective Efficacy ◽

Shigella Flexneri ◽

Content Type ◽

Immune Correlates ◽

Study Results ◽

Combination Vaccines ◽

Series Of Experiments

ABSTRACTSeveral animal models exist to evaluate the immunogenicity and protective efficacy of candidateShigellavaccines. The two most widely used nonprimate models for vaccine development include a murine pulmonary challenge model and a guinea pig keratoconjunctivitis model. Nonhuman primate models exhibit clinical features and gross and microscopic colonic lesions that mimic those induced in human shigellosis. Challenge models for enterotoxigenicEscherichia coli(ETEC) andCampylobacterspp. have been successfully developed withAotus nancymaae, and the addition of aShigella-Aotuschallenge model would facilitate the testing of combination vaccines. A series of experiments were designed to identify the dose ofShigella flexneri2a strain 2457T that induces an attack rate of 75% in theAotusmonkey. After primary challenge, the dose required to induce an attack rate of 75% was calculated to be 1 × 1011CFU.Shigella-specific immune responses were low after primary challenge and subsequently boosted upon rechallenge. However, preexisting immunity derived from the primary challenge was insufficient to protect against the homologousShigellaserotype. A successive study inA. nancymaaeevaluated the ability of multiple oral immunizations with live-attenuatedShigellavaccine strain SC602 to protect against challenge. After three oral immunizations, animals were challenged withS. flexneri2a 2457T. A 70% attack rate was demonstrated in control animals, whereas animals immunized with vaccine strain SC602 were protected from challenge (efficacy of 80%;P= 0.05). The overall study results indicate that theShigella-Aotus nancymaaechallenge model may be a valuable tool for evaluating vaccine efficacy and investigating immune correlates of protection.

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Antibody Recognition of the Dengue Virus Proteome and Implications for Development of Vaccines

Clinical and Vaccine Immunology ◽

10.1128/cvi.00016-11 ◽

2011 ◽

Vol 18 (4) ◽

pp. 523-532 ◽

Cited By ~ 14

Author(s):

Stefan Fernandez ◽

Emily D. Cisney ◽

Alexander P. Tikhonov ◽

Barry Schweitzer ◽

Robert J. Putnak ◽

...

Keyword(s):

Dengue Virus ◽

Vaccine Development ◽

Rhesus Macaques ◽

Protein Microarray ◽

Vaccination Strategy ◽

Antibody Responses ◽

Wild Type ◽

Antibody Recognition ◽

Immune Correlates ◽

The Tropics

ABSTRACTDengue is a mosquito-borne infection caused by four distinct serotypes of dengue virus, each appearing cyclically in the tropics and subtropics along the equator. Although vaccines are currently under development, none are available to the general population. One of the main impediments to the successful advancement of these vaccines is the lack of well-defined immune correlates of protection. Here, we describe a protein microarray approach for measuring antibody responses to the complete viral proteome comprised of the structural (capsid, membrane, and envelope) and nonstructural (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) components of all four dengue virus serotypes (1 to 4). We examined rhesus macaques vaccinated with tetravalent vaccines consisting of live-attenuated virus (LAV) or purified inactivated virus (PIV), followed by boosting with LAV and challenging with wild-type dengue virus. We detected temporal increases in antibodies against envelope proteins in response to either vaccine, while only the PIV/LAV vaccination strategy resulted in anticapsid antibodies. In contrast to results from vaccination, naïve macaques challenged with wild-type viruses of each serotype demonstrated a balanced response to nonstructural and structural components, including responses against the membrane protein. Our results demonstrate discriminating details concerning the nature of antibody responses to dengue virus at the proteomic level and suggest the usefulness of this information for vaccine development.

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

npj Vaccines ◽

10.1038/s41541-021-00410-8 ◽

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.

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Evaluating Use Cases for Human Challenge Trials in Accelerating SARS-CoV-2 Vaccine Development

Clinical Infectious Diseases ◽

10.1093/cid/ciaa935 ◽

2020 ◽

Cited By ~ 4

Author(s):

Linh Chi Nguyen ◽

Christopher W Bakerlee ◽

T Greg McKelvey ◽

Sophie M Rose ◽

Alexander J Norman ◽

...

Keyword(s):

Immune Response ◽

Vaccine Development ◽

Use Cases ◽

Stages Of Development ◽

Challenge Virus ◽

Vaccine Candidates ◽

Correlates Of Protection ◽

Human Immune Response ◽

Human Immune ◽

Potential Use

Abstract Human challenge trials (HCTs) have been proposed as a means to accelerate SARS-CoV-2 vaccine development. We identify and discuss 3 potential use cases of HCTs in the current pandemic: evaluating efficacy, converging on correlates of protection, and improving understanding of pathogenesis and the human immune response. We outline the limitations of HCTs and find that HCTs are likely to be most useful for vaccine candidates currently in preclinical stages of development. We conclude that, while currently limited in their application, there are scenarios in which HCTs would be extremely beneficial. Therefore, the option of conducting HCTs to accelerate SARS-CoV-2 vaccine development should be preserved. As HCTs require many months of preparation, we recommend an immediate effort to (1) establish guidelines for HCTs for COVID-19; (2) take the first steps toward HCTs, including preparing challenge virus and making preliminary logistical arrangements; and (3) commit to periodically re-evaluating the utility of HCTs.

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African Green Monkeys Recapitulate the Clinical Experience with Replication of Live Attenuated Pandemic Influenza Virus Vaccine Candidates

Journal of Virology ◽

10.1128/jvi.00425-14 ◽

2014 ◽

Vol 88 (14) ◽

pp. 8139-8152 ◽

Cited By ~ 21

Author(s):

Yumiko Matsuoka ◽

Amorsolo Suguitan ◽

Marlene Orandle ◽

Myeisha Paskel ◽

Kobporn Boonnak ◽

...

Keyword(s):

Influenza Virus ◽

Animal Models ◽

Avian Influenza ◽

Immune Responses ◽

Respiratory Tract ◽

Nonhuman Primate ◽

Protective Efficacy ◽

Wild Type ◽

Vaccine Candidates ◽

Green Monkeys

ABSTRACTLive attenuated cold-adapted (ca) H5N1, H7N3, H6N1, and H9N2 influenza vaccine viruses replicated in the respiratory tract of mice and ferrets, and 2 doses of vaccines were immunogenic and protected these animals from challenge infection with homologous and heterologous wild-type (wt) viruses of the corresponding subtypes. However, when these vaccine candidates were evaluated in phase I clinical trials, there were inconsistencies between the observations in animal models and in humans. The vaccine viruses did not replicate well and immune responses were variable in humans, even though the study subjects were seronegative with respect to the vaccine viruses before vaccination. Therefore, we sought a model that would better reflect the findings in humans and evaluated African green monkeys (AGMs) as a nonhuman primate model. The distribution of sialic acid (SA) receptors in the respiratory tract of AGMs was similar to that in humans. We evaluated the replication ofwtandcaviruses of avian influenza (AI) virus subtypes H5N1, H6N1, H7N3, and H9N2 in the respiratory tract of AGMs. All of thewtviruses replicated efficiently, while replication of thecavaccine viruses was restricted to the upper respiratory tract. Interestingly, the patterns and sites of virus replication differed among the different subtypes. We also evaluated the immunogenicity and protective efficacy of H5N1, H6N1, H7N3, and H9N2cavaccines. Protection fromwtvirus challenge correlated well with the level of serum neutralizing antibodies. Immune responses were slightly better when vaccine was delivered by both intranasal and intratracheal delivery than when it was delivered intranasally by sprayer. We conclude that live attenuated pandemic influenza virus vaccines replicate similarly in AGMs and human subjects and that AGMs may be a useful model to evaluate the replication ofcavaccine candidates.IMPORTANCEFerrets and mice are commonly used for preclinical evaluation of influenza vaccines. However, we observed significant inconsistencies between observations in humans and in these animal models. We used African green monkeys (AGMs) as a nonhuman primate (NHP) model for a comprehensive and comparative evaluation of pairs of wild-type and pandemic live attenuated influenza virus vaccines (pLAIV) representing four subtypes of avian influenza viruses and found that pLAIVs replicate similarly in AGMs and humans and that AGMs can be useful for evaluation of the protective efficacy of pLAIV.

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Elicitation of Protective Antibodies against a Broad Panel of H1N1 Viruses in Ferrets Preimmune to Historical H1N1 Influenza Viruses

Journal of Virology ◽

10.1128/jvi.01283-17 ◽

2017 ◽

Vol 91 (24) ◽

Cited By ~ 26

Author(s):

Donald M. Carter ◽

Christopher A. Darby ◽

Scott K. Johnson ◽

Michael A. Carlock ◽

Greg A. Kirchenbaum ◽

...

Keyword(s):

Animal Models ◽

Immune Responses ◽

Influenza Vaccine ◽

Animal Studies ◽

Protective Efficacy ◽

H1n1 Influenza ◽

Influenza Viruses ◽

Wild Type ◽

Vaccine Candidates ◽

Naive Animal

ABSTRACT Most preclinical animal studies test influenza vaccines in immunologically naive animal models, even though the results of vaccination may not accurately reflect the effectiveness of vaccine candidates in humans that have preexisting immunity to influenza. In this study, novel, broadly reactive influenza vaccine candidates were assessed in preimmune ferrets. These animals were infected with different H1N1 isolates before being vaccinated or infected with another influenza virus. Previously, our group has described the design and characterization of computationally optimized broadly reactive hemagglutinin (HA) antigens (COBRA) for H1N1 isolates. Vaccinating ferrets with virus-like particle (VLP) vaccines expressing COBRA HA proteins elicited antibodies with hemagglutination inhibition (HAI) activity against more H1N1 viruses in the panel than VLP vaccines expressing wild-type HA proteins. Specifically, ferrets infected with the 1986 virus and vaccinated with a single dose of the COBRA HA VLP vaccines elicited antibodies with HAI activity against 11 to 14 of the 15 H1N1 viruses isolated between 1934 and 2013. A subset of ferrets was infected with influenza viruses expressing the COBRA HA antigens. These COBRA preimmune ferrets had superior breadth of HAI activity after vaccination with COBRA HA VLP vaccines than COBRA preimmune ferrets vaccinated with VLP vaccines expressing wild-type HA proteins. Overall, priming naive ferrets with COBRA HA based viruses or using COBRA HA based vaccines to boost preexisting antibodies induced by wild-type H1N1 viruses, COBRA HA antigens elicited sera with the broadest HAI reactivity against multiple antigenic H1N1 viral variants. This is the first report demonstrating the effectiveness of a broadly reactive or universal influenza vaccine in a preimmune ferret model. IMPORTANCE Currently, many groups are testing influenza vaccine candidates to meet the challenge of developing a vaccine that elicits broadly reactive and long-lasting protective immune responses. The goal of these vaccines is to stimulate immune responses that react against most, if not all, circulating influenza strains, over a long period of time in all populations of people. Commonly, these experimental vaccines are tested in naive animal models that do not have anti-influenza immune responses; however, humans have preexisting immunity to influenza viral antigens, particularly antibodies to the HA and NA glycoproteins. Therefore, this study investigated how preexisting antibodies to historical influenza viruses influenced HAI-specific antibodies and protective efficacy using a broadly protective vaccine candidate.

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Extended Safety and Efficacy Studies of the Attenuated Brucella Vaccine Candidates 16MΔvjbRand S19ΔvjbRin the Immunocompromised IRF-1−/−Mouse Model

Clinical and Vaccine Immunology ◽

10.1128/cvi.05321-11 ◽

2011 ◽

Vol 19 (2) ◽

pp. 249-260 ◽

Cited By ~ 9

Author(s):

A. M. Arenas-Gamboa ◽

A. C. Rice-Ficht ◽

Y. Fan ◽

M. M. Kahl-McDonagh ◽

T. A. Ficht

Keyword(s):

Mouse Model ◽

Brucella Melitensis ◽

Protective Efficacy ◽

Pathological Changes ◽

Wild Type ◽

Live Attenuated Vaccine ◽

Content Type ◽

Vaccine Candidates ◽

Multiple Organs ◽

Efficacious Vaccine

ABSTRACTThe global distribution of brucellosis and high incidence in certain areas of the world warrant the development of a safer and efficacious vaccine. For the past 10 years, we have focused our attention on the development of a safer, but still highly protective, live attenuated vaccine for human and animal use. We have demonstrated the safety and protective efficacy of the vaccine candidates 16MΔvjbRand S19ΔvjbRagainst homologous and heterologous challenge in multiple immunocompetent animal models, including mice and deer. In the present study, we conducted a series of experiments to determine the safety of the vaccine candidates in interferon regulatory factor-1-knockout (IRF-1−/−) mice. IRF-1−/−mice infected with either wild-typeBrucella melitensis16M or the vaccine strainBrucella abortusS19 succumb to the disease within the first 3 weeks of infection, which is characterized by a marked granulomatous and neutrophilic inflammatory response that principally targets the spleen and liver. In contrast, IRF-1−/−mice inoculated with either the 16MΔvjbRor S19ΔvjbRvaccine do not show any clinical or major pathological changes associated with vaccination. Additionally, when 16MΔvjbR- or S19ΔvjbR-vaccinated mice are challenged with wild-typeBrucella melitensis16M, the degree of colonization in multiple organs, along with associated pathological changes, is significantly reduced. These findings not only demonstrate the safety and protective efficacy of thevjbRmutant in an immunocompromised mouse model but also suggest the participation of lesser-known mechanisms in protective immunity against brucellosis.

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Passive immunisation of convalescent human anti-Zika plasma protects against challenge with New World Zika virus in cynomolgus macaques

npj Vaccines ◽

10.1038/s41541-020-00234-y ◽

2020 ◽

Vol 5 (1) ◽

Author(s):

Neil Berry ◽

Sarah Kempster ◽

Claire Ham ◽

Adrian Jenkins ◽

Jo Hall ◽

...

Keyword(s):

Zika Virus ◽

Vaccine Development ◽

De Novo ◽

Protective Efficacy ◽

Lymphoid Tissues ◽

Passive Immunisation ◽

Post Challenge ◽

Virus Challenge ◽

Immune Correlates ◽

Cynomolgus Macaques

Abstract Zika virus (ZIKV) causes neurological complications in susceptible individuals, highlighted in the recent South American epidemic. Natural ZIKV infection elicits host responses capable of preventing subsequent re-infection, raising expectations for effective vaccination. Defining protective immune correlates will inform viral intervention strategies, particularly vaccine development. Non-human primate (NHP) species are susceptible to ZIKV and represent models for vaccine development. The protective efficacy of a human anti-ZIKV convalescent plasma pool (16/320-14) developed as a candidate reference material for a WHO International Standard was evaluated in macaques. Convalescent plasma administered to four cynomolgus macaques (Macaca fascicularis) intra-peritoneally 24 hrs prior to sub-cutaneous challenge with 103 pfu ZIKVPRVABC59 protected against detectable infection, with absence of detectable ZIKV RNA in blood and lymphoid tissues. Passively immunised anti-ZIKV immunoglobulin administered prior to time of challenge remained present only at very low levels 42 days post-challenge. Absence of de novo antibody responses in passively immunised macaques indicate sterilising immunity compared with naïve challenge controls that exhibited active ZIKV-specific IgM and IgG responses post-challenge. Demonstration that the presence of convalescent anti-ZIKV at levels of 400 IU/mL neutralising antibody protects against virus challenge provides a scientific framework for development of anti-ZIKV vaccines and facilitates regulatory approval.

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