Major Areas of Research
- Study viral pathogenesis and immune responses in animal models
- Identify and prioritize potential pandemic strains of influenza to target for vaccine development
- Generate attenuated vaccine viruses by reassortment or plasmid-based reverse genetics
- Evaluate antigenic relatedness and cross-protection between influenza viruses
- Evaluate candidate vaccine viruses in preclinical studies in animal models
- Conduct clinical evaluation of suitable candidate vaccines to establish safety, immunogenicity, and infectivity of live, attenuated vaccines
Our research is focused on understanding the pathogenesis of influenza and the development of vaccines against pandemic strains of influenza.
Group 2 HA Stem-immunogen (SI) Vaccines Expressed in Escherichia coli
Collaborated with Dr. Raghavan Varadarajan from the Molecular Biophysics Unit at the Indian Institute of Science, Bangalore, India, to evaluate engineered group 2 HA stem-immunogen (SI) vaccines expressed in Escherichia coli for their immunogenicity and efficacy in mice and ferrets. Immunization induced antibodies that bound to recombinant HA protein and viral particles and competed with the broadly neutralizing monoclonal antibody, CR9114, for binding to the HA stem. Mice vaccinated with H3 and H7-SI were protected from lethal homologous challenge and displayed moderate heterologous protection. Ferrets developed lower titers of antibodies that bound a narrow range of HA stem epitopes compared to mice. Collectively, group 2 SI vaccines show promise, with further optimization to enhance the immunogenicity and efficacy in ferrets. Manuscript submitted to Nature Microbiology.
Nonreplicating Influenza A Virus
Collaborating with Dr. Alain Townsend from the Human Immunology Unit at the Weatherall Institute, University of Oxford to evaluate the ability of a nonreplicating influenza A virus to induce broadly cross-protective immunity against a range of influenza A viruses. We have previously demonstrated (Baz et al mBio 6: e01487-15, 2015) that S-Flu vaccine viruses, based on suppression of the HA signal sequence, elicited robust protection against homologous and heterosubtypic challenge in mice and ferrets, comparable to live attenuated influenza vaccines. We have extended these findings to demonstrate that a group 2 S-Flu vaccine virus can suppress replication and transmission of a group 1 challenge virus in ferrets. These data suggest that pseudotyped nonreplicating influenza viruses warrant further development and evaluation in humans.
Pandemic Live Attenuated Influenza Vaccine (pLAIV) Viruses
Under a CRADA with MedImmune, ERVS scientists have developed and evaluated a series of pandemic live attenuated influenza vaccine (pLAIV) viruses and have demonstrated with H5N1, H7N7 and H7N9 vaccines that they induce long-lasting, immunity that can be rapidly recalled (within 7 days) with a dose of inactivated subunit vaccine (ISV). The antibody is of high quality and is broadly reactive within subtype (J Infect Dis 2014; 209:1860-9; Vaccine 2014; 32:6798-804; J Infect Dis 2016; 213:922-9). We have demonstrated that the interval between pLAIV priming and pISV boost can be as short as 4 weeks (manuscript in preparation). We are currently investigating the importance of antigenic match between the pLAIV and pISV and whether the use of adjuvanted pISV will allow us to prime with a single dose of pLAIV.
Also under a CRADA with MedImmune, we have developed and evaluated a series of pandemic live attenuated influenza vaccine (pLAIV) viruses and are undertaking a study to determine whether pandemic ISV can boost the HA stalk antibody response in people who have previously received a pLAIV. This study will be conducted under a clinical contract at the Johns Hopkins University Bloomberg School of Public Health.
HA Stem Antibody MEDI8852
Collaborated with scientists at MedImmune to evaluate an HA stem antibody MEDI8852, a novel monoclonal antibody that neutralizes both group 1 and group 2 influenza A viruses in vitro. We demonstrated that MEDI8852, alone or with oseltamivir, shows promise for prophylaxis or therapy of group 1 and 2 influenza viruses with pandemic potential. Additionally, MEDI8852 blocked influenza transmission in ferrets, a unique finding among influenza specific monoclonal antibodies. Manuscript under review at the Journal of Infectious Diseases.
Broadly Neutralizing Hemagglutinin Stem-binding Antibodies
Collaborated with scientists at Janssen who had developed broadly neutralizing hemagglutinin stem-binding antibodies that showed weak in vitro activity against human H2 influenza viruses, but their in vivo efficacy against H2 viruses was unknown. We evaluated these antibodies against human and animal origin H2 viruses and showed that both antibodies reduced mortality, weight loss, airway inflammation, and pulmonary viral load that was partially mediated by Fc-receptor dependent mechanisms. Our findings demonstrated the efficacy of CR6261 and CR9114 against H2 viruses in a mouse model. Manuscript in preparation.
Emerito Amaro-Carambot; Corey Balinksky; Rita Czako Stinnett; Cai-Yen Firestone; Katherine Houser; Elaine Lamirande; Yumiko Matsuoka; Myeisha Paskel; Celia Santos; Troy Sutton; Leatrice Vogel; Stephen Whitehead, Ph.D.