A proof of concept for structure-based vaccine design targeting RSV in humans

Science ◽  
2019 ◽  
Vol 365 (6452) ◽  
pp. 505-509 ◽  
Author(s):  
Michelle C. Crank ◽  
Tracy J. Ruckwardt ◽  
Man Chen ◽  
Kaitlyn M. Morabito ◽  
Emily Phung ◽  
...  
Keyword(s):  
Subunit Vaccine ◽  
Vaccine Development ◽  
Vaccine Candidate ◽  
Level Structure ◽  
Vaccine Design ◽  
Atomic Level ◽  
Surface Proteins ◽  
Proof Of Concept ◽  
Syncytial Virus ◽  
Viral Surface

Technologies that define the atomic-level structure of neutralization-sensitive epitopes on viral surface proteins are transforming vaccinology and guiding new vaccine development approaches. Previously, iterative rounds of protein engineering were performed to preserve the prefusion conformation of the respiratory syncytial virus (RSV) fusion (F) glycoprotein, resulting in a stabilized subunit vaccine candidate (DS-Cav1), which showed promising results in mice and macaques. Here, phase I human immunogenicity data reveal a more than 10-fold boost in neutralizing activity in serum from antibodies targeting prefusion-specific surfaces of RSV F. These findings represent a clinical proof of concept for structure-based vaccine design, suggest that development of a successful RSV vaccine will be feasible, and portend an era of precision vaccinology.

scholarly journals Structure-Based Vaccine Antigen Design

2019 ◽  
Vol 70 (1) ◽  
pp. 91-104 ◽  
Author(s):  
Barney S. Graham ◽  
Morgan S.A. Gilman ◽  
Jason S. McLellan
Keyword(s):  
Vaccine Development ◽  
Structural Information ◽  
Protein Structures ◽  
Surface Protein ◽  
Surface Proteins ◽  
Vaccine Antigen ◽  
Viral Fusion ◽  
Emerging Pathogens ◽  
Syncytial Virus ◽  
Viral Surface

Enabled by new approaches for rapid identification and selection of human monoclonal antibodies, atomic-level structural information for viral surface proteins, and capacity for precision engineering of protein immunogens and self-assembling nanoparticles, a new era of antigen design and display options has evolved. While HIV-1 vaccine development has been a driving force behind these technologies and concepts, clinical proof-of-concept for structure-based vaccine design may first be achieved for respiratory syncytial virus (RSV), where conformation-dependent access to neutralization-sensitive epitopes on the fusion glycoprotein determines the capacity to induce potent neutralizing activity. Success with RSV has motivated structure-based stabilization of other class I viral fusion proteins for use as immunogens and demonstrated the importance of structural information for developing vaccines against other viral pathogens, particularly difficult targets that have resisted prior vaccine development efforts. Solving viral surface protein structures also supports rapid vaccine antigen design and application of platform manufacturing approaches for emerging pathogens.

scholarly journals Searching for an ideal vaccine candidate among different MERS coronavirus receptor-binding fragments—The importance of immunofocusing in subunit vaccine design

Vaccine ◽  
2014 ◽  
Vol 32 (46) ◽  
pp. 6170-6176 ◽  
Author(s):  
Cuiqing Ma ◽  
Lili Wang ◽  
Xinrong Tao ◽  
Naru Zhang ◽  
Yang Yang ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Subunit Vaccine ◽  
Vaccine Candidate ◽  
Vaccine Design ◽  
Ideal Vaccine

scholarly journals Application of Viral Vectors for Vaccine Development with a Special Emphasis on COVID-19

Viruses ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1324
Author(s):  
Kenneth Lundstrom
Keyword(s):  
Neutralizing Antibodies ◽  
Viral Vectors ◽  
Vaccine Development ◽  
Viral Vector ◽  
Recombinant Protein Expression ◽  
Surface Proteins ◽  
Viral Particles ◽  
Preclinical Animal Models ◽  
Viral Surface ◽  
Lethal Doses

Viral vectors can generate high levels of recombinant protein expression providing the basis for modern vaccine development. A large number of different viral vector expression systems have been utilized for targeting viral surface proteins and tumor-associated antigens. Immunization studies in preclinical animal models have evaluated the elicited humoral and cellular responses and the possible protection against challenges with lethal doses of infectious pathogens or tumor cells. Several vaccine candidates for both infectious diseases and various cancers have been subjected to a number of clinical trials. Human immunization trials have confirmed safe application of viral vectors, generation of neutralizing antibodies and protection against challenges with lethal doses. A special emphasis is placed on COVID-19 vaccines based on viral vectors. Likewise, the flexibility and advantages of applying viral particles, RNA replicons and DNA replicon vectors of self-replicating RNA viruses for vaccine development are presented.

Respiratory syncytial virus protein structure, function and implications for subunit vaccine development

2014 ◽  
Vol 9 (8) ◽  
pp. 753-767 ◽  
Author(s):  
Michael McCarthy ◽  
Tonya Villafana ◽  
Elizabeth Stillman ◽  
Mark T Esser
Keyword(s):  
Respiratory Syncytial Virus ◽  
Protein Structure ◽  
Structure Function ◽  
Subunit Vaccine ◽  
Vaccine Development ◽  
Virus Protein ◽  
Syncytial Virus

Influence of administration dose and route on the immunogenicity and protective efficacy of BBG2Na, a recombinant respiratory syncytial virus subunit vaccine candidate

Vaccine ◽  
2000 ◽  
Vol 18 (24) ◽  
pp. 2735-2742 ◽  
Author(s):  
Liliane Goetsch ◽  
Hélène Plotnicky-Gilquin ◽  
Thierry Champion ◽  
Alain Beck ◽  
Nathalie Corvaı̈a ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Subunit Vaccine ◽  
Vaccine Candidate ◽  
Protective Efficacy ◽  
Syncytial Virus

scholarly journals The potential for antibody-dependent enhancement of SARS-CoV-2 infection: Translational implications for vaccine development

2020 ◽  
pp. 1-4 ◽  
Author(s):  
Jiong Wang ◽  
Martin S. Zand
Keyword(s):  
Monoclonal Antibody ◽  
Virus Infection ◽  
Dengue Virus ◽  
Vaccine Development ◽  
Surface Proteins ◽  
Dengue Virus Infection ◽  
Antibody Dependent Enhancement ◽  
High Affinity ◽  
Viral Surface

Abstract There is an urgent need for vaccines to the 2019 coronavirus (COVID19; SARS-CoV-2). Vaccine development may not be straightforward, due to antibody-dependent enhancement (ADE). Antibodies against viral surface proteins can, in some cases, increase infection severity by ADE. This phenomenon occurs in SARS-CoV-1, MERS, HIV, Zika, and dengue virus infection and vaccination. Lack of high-affinity anti-SARS-CoV-2 IgG in children may explain the decreased severity of infection in these groups. Here, we discuss the evidence for ADE in the context of SARS-CoV-2 infection and how to address this potential translational barrier to vaccine development, convalescent plasma, and targeted monoclonal antibody therapies.

ChAd155-RSV vaccine is immunogenic and efficacious against bovine RSV infection-induced disease in young calves

2021 ◽  
Author(s):  
Rineke de Jong ◽  
Norbert Stockhofe-Zurwieden ◽  
Judith Bonsing ◽  
Kai-fen Wang ◽  
Sarah Vandepaer ◽  
...  
Keyword(s):  
Vaccine Development ◽  
Vaccine Candidate ◽  
Clinical Symptoms ◽  
Clinical Signs ◽  
Clinical Manifestations ◽  
Neutralizing Antibody ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
Tract Disease ◽  
The One

Abstract Respiratory syncytial virus (RSV) infection causes a substantial lower respiratory-tract disease burden in infants, and is a global priority for vaccine development. We evaluated the immunogenicity, safety and efficacy of a chimpanzee adenovirus (ChAd)-based vaccine candidate, ChAd155-RSV, in a bovine RSV (bRSV) challenge model. This model closely reproduces the pathogenesis/clinical manifestations of severe pediatric RSV disease. In seronegative calves, ChAd155-RSV elicited robust neutralizing antibody responses against human RSV. Two doses protected calves from clinical symptoms/lung pathological changes, and reduced nasal/lung virus loads after both a short (4-week) and a long (16-week) interval between the last immunization and a subsequent bRSV challenge. The one-dose regimen also conferred near-complete or significant protection after the short-term or long-term intervals before challenge, respectively. Importantly, immunized calves presented no clinical signs of enhanced respiratory disease. Collectively, the data supported the development of ChAd155-RSV as an RSV vaccine candidate for infants.

scholarly journals Immunization with Low Doses of Recombinant Postfusion or Prefusion Respiratory Syncytial Virus F Primes for Vaccine-Enhanced Disease in the Cotton Rat Model Independently of the Presence of a Th1-Biasing (GLA-SE) or Th2-Biasing (Alum) Adjuvant

2017 ◽  
Vol 91 (8) ◽  
Author(s):  
Kirsten Schneider-Ohrum ◽  
Corinne Cayatte ◽  
Angie Snell Bennett ◽  
Gaurav Manohar Rajani ◽  
Patrick McTamney ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Virus Replication ◽  
Rat Model ◽  
Neutralizing Antibodies ◽  
Subunit Vaccine ◽  
Vaccine Candidate ◽  
Dose Range ◽  
Vaccine Candidates ◽  
Cotton Rat ◽  
Syncytial Virus

ABSTRACT Respiratory syncytial virus (RSV) infection of children previously immunized with a nonlive, formalin-inactivated (FI)-RSV vaccine has been associated with serious enhanced respiratory disease (ERD). Consequently, detailed studies of potential ERD are a critical step in the development of nonlive RSV vaccines targeting RSV-naive children and infants. The fusion glycoprotein (F) of RSV in either its postfusion (post-F) or prefusion (pre-F) conformation is a target for neutralizing antibodies and therefore an attractive antigen candidate for a pediatric RSV subunit vaccine. Here, we report the evaluation of RSV post-F and pre-F in combination with glucopyranosyl lipid A (GLA) integrated into stable emulsion (SE) (GLA-SE) and alum adjuvants in the cotton rat model. Immunization with optimal doses of RSV F antigens in the presence of GLA-SE induced high titers of virus-neutralizing antibodies and conferred complete lung protection from virus challenge, with no ERD signs in the form of alveolitis. To mimic a waning immune response, and to assess priming for ERD under suboptimal conditions, an antigen dose de-escalation study was performed in the presence of either GLA-SE or alum. At low RSV F doses, alveolitis-associated histopathology was unexpectedly observed with either adjuvant at levels comparable to FI-RSV-immunized controls. This occurred despite neutralizing-antibody titers above the minimum levels required for protection and with no/low virus replication in the lungs. These results emphasize the need to investigate a pediatric RSV vaccine candidate carefully for priming of ERD over a wide dose range, even in the presence of strong neutralizing activity, Th1 bias-inducing adjuvant, and protection from virus replication in the lower respiratory tract. IMPORTANCE RSV disease is of great importance worldwide, with the highest burden of serious disease occurring upon primary infection in infants and children. FI-RSV-induced enhanced disease, observed in the 1960s, presented a major and ongoing obstacle for the development of nonlive RSV vaccine candidates. The findings presented here underscore the need to evaluate a nonlive RSV vaccine candidate during preclinical development over a wide dose range in the cotton rat RSV enhanced-disease model, as suboptimal dosing of several RSV F subunit vaccine candidates led to the priming for ERD. These observations are relevant to the validity of the cotton rat model itself and to safe development of nonlive RSV vaccines for seronegative infants and children.

scholarly journals Potential Mechanisms of Age Related Severity of COVID-19 Infection: Implications for Development of Vaccines, Convalescent Serum, and Antibody Therapies

2020 ◽  
Author(s):  
Martin Zand ◽  
Jiong Wang
Keyword(s):  
Viral Entry ◽  
Vaccine Development ◽  
Surface Proteins ◽  
Igg Antibodies ◽  
Dengue Virus Infection ◽  
Younger Adults ◽  
High Affinity ◽  
Age Related ◽  
Coronavirus Infection ◽  
Viral Surface

There is an urgent need for vaccines to induce immunity to the 2019 coronavirus strain (COVID-19; CoV-SARS-2). Vaccine development may not be straightforward, in part due to the the phenomenon of antibody-dependent enhancement (ADE). The immune response to coronavirus infection or vaccination generates a mixture of IgG antibodies against viral surface proteins. Many of these antibodies block viral infection. However, in some cases IgG:virus complexes can facilitate viral entry and infection of cells by ADE, increasing the the risk and severity of infection. This phenomenon occurs in SARS, MERS, HIV, Zika and dengue virus infection and vaccination; it has been a serious barrier to vaccine development for these infections. Lack of high-affinity anti-COVID-19 IgG antibodies in children and younger adults may explain, in part, the decreased severity of infection in these groups. Here, we discuss the evidence for ADE in the context of COVID-19 infection, and how it may affect development of a vaccine and convalescent serum therapies. Here we discuss ADE in the context of COVID-19 infection, and how this may affect vaccine development, convalescent serum, and targeted monoclonal antibody therapies. We caution that this work is a hypothesis, and should be taken as such.

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