Respiratory syncytial virus elicits enriched CD8+ T lymphocyte responses in lung compared with blood in African green monkeys

PLOS ONE, Nov 2019

Respiratory syncytial virus (RSV) is a leading cause of serious lower respiratory tract disease in young children and older adults throughout the world. Prevention of severe RSV disease through active immunization is optimal but no RSV vaccine has been licensed so far. Immune mechanisms of protection against RSV infection in humans have not been fully established, thus a comprehensive characterization of virus-specific immune responses in a relevant animal model will be beneficial in defining correlates of protection. In this study, we infected juvenile naive AGMs with RSV A2 strain and longitudinally assessed virus-specific humoral and cellular immune responses in both peripheral blood and the respiratory tract. RSV viral loads at nasopharyngeal surfaces and in the lung peaked at around day 5 following infection, and then largely resolved by day 10. Low levels of neutralizing antibody titers were detected in serum, with similar kinetics as RSV fusion (F) protein-binding IgG antibodies. RSV infection induced CD8+, but very little CD4+, T lymphocyte responses in peripheral blood. Virus-specific CD8+ T cell frequencies were ~10 fold higher in bronchoaveolar lavage (BAL) compared to peripheral blood and exhibited effector memory (CD95+CD28-) / tissue resident memory (CD69+CD103+) T (TRM) cell phenotypes. The kinetics of virus-specific CD8+ T cells emerging in peripheral blood and BAL correlated with declining viral titers, suggesting that virus-specific cellular responses contribute to the clearance of RSV infection. RSV-experienced AGMs were protected from subsequent exposure to RSV infection. Additional studies are underway to understand protective correlates in these seropositive monkeys.

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Respiratory syncytial virus elicits enriched CD8+ T lymphocyte responses in lung compared with blood in African green monkeys

November Respiratory syncytial virus elicits enriched CD8+ T lymphocyte responses in lung compared with blood in African green monkeys Hualin Li 0 1 Cheryl Callahan 0 1 Michael Citron 0 1 Zhiyun Wen 0 1 Sinoeun Touch 0 1 Morgan A. Monslow 0 1 Kara S. Cox 0 1 Daniel J. DiStefano 0 1 Kalpit A. Vora 0 1 Andrew Bett 0 1 Amy Espeseth 0 1 0 Department of Infectious Diseases and Vaccines, MRL, Merck & Co., Inc. , West Point, PA , United States of America 1 Editor: Steven M. Varga, University of Iowa , UNITED STATES Respiratory syncytial virus (RSV) is a leading cause of serious lower respiratory tract disease in young children and older adults throughout the world. Prevention of severe RSV disease through active immunization is optimal but no RSV vaccine has been licensed so far. Immune mechanisms of protection against RSV infection in humans have not been fully established, thus a comprehensive characterization of virus-specific immune responses in a relevant animal model will be beneficial in defining correlates of protection. In this study, we infected juvenile naive AGMs with RSV A2 strain and longitudinally assessed virus-specific humoral and cellular immune responses in both peripheral blood and the respiratory tract. RSV viral loads at nasopharyngeal surfaces and in the lung peaked at around day 5 following infection, and then largely resolved by day 10. Low levels of neutralizing antibody titers were detected in serum, with similar kinetics as RSV fusion (F) protein-binding IgG antibodies. RSV infection induced CD8+, but very little CD4+, T lymphocyte responses in peripheral blood. Virus-specific CD8+ T cell frequencies were ~10 fold higher in bronchoaveolar lavage (BAL) compared to peripheral blood and exhibited effector memory (CD95+CD28-) / tissue resident memory (CD69+CD103+) T (TRM) cell phenotypes. The kinetics of virus-specific CD8+ T cells emerging in peripheral blood and BAL correlated with declining viral titers, suggesting that virus-specific cellular responses contribute to the clearance of RSV infection. RSV-experienced AGMs were protected from subsequent exposure to RSV infection. Additional studies are underway to understand protective correlates in these seropositive monkeys. Data Availability Statement; All relevant data are within the paper - Funding: The research was fully funded by Merck & Co., Inc. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: All authors are employees of Merck & Co., Inc. This commercial affiliation does not alter the authors' adherence to all PLOS ONE policies on sharing data and materials. Introduction Human respiratory syncytial virus (RSV) has been identified as the leading cause of severe respiratory disease in infants [ 1 ]. Severe RSV illness commonly occurs among infants with primary infection in the first year of life, and most infants have experienced a primary RSV infection by age two [ 2 ]. Globally, it is estimated that RSV infection results in 64 million acute respiratory infection cases and 160,000 deaths annually [ 1 ]. While healthy young adults generally only suffer common cold symptoms and are at low risk of severe disease, adults with underlying diseases, such as COPD or asthma, or those who are immune-compromised, are also at a high risk of developing severe RSV infection [3±5]. In addition, RSV has been recognized in recent years as a significant problem in debilitated and elderly persons and infection may lead to cardiac failure and secondary bacterial pneumonia [ 5, 6 ]. RSV can cause severe lower respiratory complications in older adults, resulting in respiratory failure, prolonged hospitalization, and high mortality similar to seasonal influenza [6]. Despite the increased appreciation of the large global impact of RSV disease, there remains no licensed active vaccine. Passive immunotherapy with RespiGam (RSV immune globulin) [ 7 ] and the RSV fusion (F) protein-specific humanized monoclonal antibody palivizumab (Synagis) [ 8 ] were approved to be used in infants at high risk of developing severe RSV lower respiratory tract infection (LRTI). However, a safe and effective vaccine would be a more cost effective solution for the prevention of RSV in at risk populations. Efforts to develop a safe and effective RSV vaccine have been largely daunted by the failure of a formalin-inactivated RSV (FI-RSV) vaccine in a clinical trial ~50 years ago [ 9 ]. Despite a recent increase in interest, investment, and progress towards development of RSV vaccines for infants and / or the elderly [ 10, 11 ], a number of challenges remain for the development of an effective RSV vaccine, including major unanswered questions surrounding the human immune responses and protection correlates to an RSV infection. Epidemiological and human challenge studies have pointed to a variety of factors associated with protection from RSV, including neutrali (...truncated)


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Hualin Li, Cheryl Callahan, Michael Citron, Zhiyun Wen, Sinoeun Touch, Morgan A. Monslow, Kara S. Cox, Daniel J. DiStefano, Kalpit A. Vora, Andrew Bett, Amy Espeseth. Respiratory syncytial virus elicits enriched CD8+ T lymphocyte responses in lung compared with blood in African green monkeys, PLOS ONE, 2017, Volume 12, Issue 11, DOI: 10.1371/journal.pone.0187642