Safe and Effective RSV Protein Vaccines

Sinu P. John, Ph.D.

Section or Unit Name
Signaling Systems Section
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Our research focuses primarily on identification of cell intrinsic factors (protein coding and non-coding genes) associated with regulation of macrophage signaling. We use high throughput genome-wide techniques such as RNAi screening, CRISPR screening, RNA-seq, ATAC-seq, etc. to identify and characterize the genes and gene-regulatory mechanisms that modulate the immune response in macrophage cells. In addition, we study the role of various external factors (environmental pollutants, drugs, diet, etc.) that modulate the immune response in macrophages with an emphasis to develop therapeutic candidates for the treatment of infectious and immune diseases. We use both bacterial and several emerging viral models such as HIV, Influenza, SARS-CoV-2, etc. to study the impact of immune regulation by various intrinsic and external factors.

Selected Publications

John SP, Singh A, Sun J, Pierre MJ, Alsalih L, Lipsey C, Traore Z, Balcom-Luker S, Bradfield CJ, Song J, Markowitz TE, Smelkinson M, Ferrer M, Fraser IDC. Small-molecule screening identifies Syk kinase inhibition and rutaecarpine as modulators of macrophage training and SARS-CoV-2 infection. Cell Rep. 2022 Oct 4;41(1):111441.

John SP, Sun J, Carlson RJ, Cao B, Bradfield CJ, Song J, Smelkinson M, Fraser IDC. IFIT1 Exerts Opposing Regulatory Effects on the Inflammatory and Interferon Gene Programs in LPS-Activated Human Macrophages. Cell Rep. 2018 Oct 2;25(1):95-106.e6.

John SP, Chin CR, Perreira JM, Feeley EM, Aker AM, Savidis G, Smith SE, Elia AE, Everitt AR, Vora M, Pertel T, Elledge SJ, Kellam P, Brass AL. The CD225 domain of IFITM3 is required for both IFITM protein association and inhibition of influenza A virus and dengue virus replication. J Virol. 2013 Jul;87(14):7837-52.

Zhu J, Gaiha GD, John SP, Pertel T, Chin CR, Gao G, Qu H, Walker BD, Elledge SJ, Brass AL. Reactivation of latent HIV-1 by inhibition of BRD4. Cell Rep. 2012 Oct 25;2(4):807-16.

Everitt AR, Clare S, Pertel T, John SP, Wash RS, Smith SE, Chin CR, Feeley EM, Sims JS, Adams DJ, Wise HM, Kane L, Goulding D, Digard P, Anttila V, Baillie JK, Walsh TS, Hume DA, Palotie A, Xue Y, Colonna V, Tyler-Smith C, Dunning J, Gordon SB; GenISIS Investigators; MOSAIC Investigators; Smyth RL, Openshaw PJ, Dougan G, Brass AL, Kellam P. IFITM3 restricts the morbidity and mortality associated with influenza. Nature. 2012 Mar 25;484(7395):519-23.

Brass AL, Huang IC, Benita Y, John SP, Krishnan MN, Feeley EM, Ryan BJ, Weyer JL, van der Weyden L, Fikrig E, Adams DJ, Xavier RJ, Farzan M, Elledge SJ. The IFITM proteins mediate cellular resistance to influenza A H1N1 virus, West Nile virus, and dengue virus. Cell. 2009 Dec 24;139(7):1243-54.

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Major Areas of Research
  • Genes and epigenetic states modulating macrophage signaling and function
  • Identification and characterization of trained immunity stimuli
  • Applications of trained immunity in infectious and immune disease

NIAID-Supported Study Provides Stronger Evidence of Link Between RSV and Childhood Asthma

NIAID Now |

A NIAID-supported study has found that respiratory syncytial virus (RSV) infection in the first year of life is associated with a significantly increased risk of asthma in children. The study was published in the journal The Lancet. These findings provide additional evidence for a casual association between the occurrence of RSV infection in children younger than 1 and an increased incidence of wheezing and asthma in later in life.

RSV is a seasonal respiratory pathogen that affects almost all children by age 2, and repeatedly throughout life. In most children, symptoms of the virus are mild and usually resolve within a week. However, RSV can lead to death or serious illness, especially in premature or very young infants, and those with chronic lung disease or congenital heart disease, although about half of all RSV hospitalizations are among healthy infants. In infants (children younger than 1), RSV is the leading cause of bronchiolitis, a lower respiratory tract infection in infants and young children presenting with coughing and wheezing. Prior evidence on the links between RSV infection in infancy and respiratory health derives from studies of children with severe RSV bronchiolitis, which impacts a minority of children. The population-level asthma risk following RSV infection of any severity has not been studied before.

The “Infant Susceptibility to Pulmonary Infections and Asthma Following RSV Exposure (INSPIRE)” is the first cohort specifically designed to test the hypothesis that not being infected with RSV in infancy decreases the risk of childhood asthma. The population-based cohort study included 1,946 healthy infants born between June and December of 2012 and 2013 who were 6 months old or younger at the beginning of the RSV season (November to March in the study area of Tennessee). Biweekly surveillance and serology tests were used to classify infants as RSV infected or not infected in the first year of life. Of the 1,741 who received classifications, 54% were infected with RSV in the first year of life.

Participants were followed prospectively for five years and then evaluated for 5-year current asthma, which was defined as 1) a parental report of diagnosed asthma or the use of asthma medications before age 5, and 2) any of the following in the 12 months prior to the 5-year visit: asthma symptoms, use of systemic (oral or intravenous) steroids for asthma, or doctor or emergency room visits for asthma symptoms.

The study found that infants who were not infected with RSV in the first year of life had a 26% lower risk of asthma at 5 years of age than those who were infected with RSV as infants. Because the study was observational, the results do not definitively establish causality but do support a need for long-term follow-up of common respiratory outcomes among children in clinical trials of RSV prevention products.

Infancy is a critical time for immune system and pulmonary development; understanding how RSV infection before age 1 is associated with an increased risk of childhood asthma could help to prevent long-term childhood respiratory morbidity.

The study was funded by NIAID, the National Heart, Lung and Blood Institute, the National Center for Advancing Translational Sciences and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Reference: C Rosas-Salazar, et al. Respiratory syncytial virus infection during infancy and asthma during childhood in the USA (INSPIRE): a population-based, prospective birth cohort study.

The Lancet DOI: 10.1016/S0140-6736(23)00811-5 (2023)

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niaidnews@niaid.nih.gov

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Developing Mucosal Vaccines for Respiratory Viruses

Vaccines that provide long-lasting protection against influenza, coronaviruses and respiratory syncytial virus (RSV) have proved exceptionally difficult to develop. In a new review article in Cell Host & Microbe, researchers from the National Institute of Allergy and Infectious Diseases (NIAID), part of the NIH, explore the challenges and outline approaches to improved vaccines. Anthony S. Fauci, M.D., former NIAID director, is an author along with Jeffery K. Taubenberger, M.D., Ph.D., and David M. Morens, M.D.

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Neeltje van Doremalen, Ph.D.

Neeltje van Doremalen, Ph.D.

Section or Unit Name
Mucosal Immunology and Virology Unit (MIVU)
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Our lab is dedicated to understanding the unique role of the mucosal immune system in protecting the respiratory tract against viral infections. Unlike the systemic immune system, the mucosal immune system acts as the first line of defense at critical surfaces such as the respiratory tract, gut, and reproductive organs. Key players in this defense include tissue-resident memory T cells and secretory IgA, which operate independently of systemic responses. We aim to unravel how mucosal immunity is induced and how it provides protection against respiratory viruses, particularly in the context of infections in the upper and lower respiratory tracts.

We investigate the immune responses elicited by respiratory viruses such as influenza A viruses and coronaviruses, focusing on both mucosal and systemic adaptive immunity. Using rodent models, we study the humoral and cellular responses elicited by different infection routes and analyze the role of innate immunity in shaping adaptive responses. By leveraging techniques like high dimensional flow cytometry, systems serology, deep mutational scanning, single-cell transcriptomics, and multiplex imaging, we gain spatial and temporal insights into immune responses across critical tissues, including the nasal-associated lymphoid tissue, nasal turbinates, lungs, and lymph nodes. These studies enable us to map mucosal immunity comprehensively and identify the breadth and depth required for protection upon rechallenge.

We additionally aim to identify correlates of protection and optimize vaccine strategies to induce robust mucosal immunity. We evaluate diverse vaccine platforms—including mRNA, vectored, and subunit vaccines—administered via various routes, such as intranasal, intramuscular, and inhalation. By comparing vaccine technologies and regimens, we aim to establish principles for designing universal vaccines capable of inducing broad, durable mucosal immune responses. Ultimately, our goal is to provide foundational insights that improve vaccine design and our understanding of protective mechanisms against respiratory viruses.

Immunohistochemistry staining of nasal-associated lymphoid tissues (NALT). The upper panels show CD3 (yellow, marking T cells) and PAX5 (teal, marking B cells). The lower panels depict Ki67 (purple, marking proliferating cells).

Immunohistochemistry staining of nasal-associated lymphoid tissues (NALT). The upper panels show CD3 (yellow, marking T cells) and PAX5 (teal, marking B cells). The lower panels depict Ki67 (purple, marking proliferating cells). Samples were collected at various time points following intranasal vaccination of mice with a replication-incompetent adenovirus vaccine. Acknowledgements: Reshma K. Mukesh, Carl Shaia, Jessy Prado-Smith.

Credit: NIAID
Immunohistochemistry staining of nasal turbinates and NALT tissues with CD3 (brown), highlighting the migration of T cells into these regions.

Immunohistochemistry staining of nasal turbinates and NALT tissues with CD3 (brown), highlighting the migration of T cells into these regions. Samples were collected at various time points after intranasal vaccination of mice with a replication-incompetent adenovirus vaccine. Acknowledgements: Reshma K. Mukesh, Carl Shaia, Jessy Prado-Smith.

Credit: NIAID
Selected Publications

Cohen AA, van Doremalen N, Greaney AJ, Andersen H, Sharma A, Starr TN, Keeffe JR, Fan C, Schulz JE, Gnanapragasam PNP, Kakutani LM, West AP Jr, Saturday G, Lee YE, Gao H, Jette CA, Lewis MG, Tan TK, Townsend AR, Bloom JD, Munster VJ, Bjorkman PJ. Mosaic RBD nanoparticles protect against challenge by diverse sarbecoviruses in animal models. Science. 2022 Aug 5;377(6606):eabq0839.

van Doremalen N, Purushotham JN, Schulz JE, Holbrook MG, Bushmaker T, Carmody A, Port JR, Yinda CK, Okumura A, Saturday G, Amanat F, Krammer F, Hanley PW, Smith BJ, Lovaglio J, Anzick SL, Barbian K, Martens C, Gilbert SC, Lambe T, Munster VJ. Intranasal ChAdOx1 nCoV-19/AZD1222 vaccination reduces viral shedding after SARS-CoV-2 D614G challenge in preclinical models. Sci Transl Med. 2021 Aug 18;13(607):eabh0755.

Holbrook MG, Anthony SJ, Navarrete-Macias I, Bestebroer T, Munster VJ, van Doremalen N. Updated and Validated Pan-Coronavirus PCR Assay to Detect All Coronavirus Genera. Viruses. 2021 Apr 1;13(4):599.

van Doremalen N, Lambe T, Spencer A, Belij-Rammerstorfer S, Purushotham JN, Port JR, Avanzato VA, Bushmaker T, Flaxman A, Ulaszewska M, Feldmann F, Allen ER, Sharpe H, Schulz J, Holbrook M, Okumura A, Meade-White K, Pérez-Pérez L, Edwards NJ, Wright D, Bissett C, Gilbride C, Williamson BN, Rosenke R, Long D, Ishwarbhai A, Kailath R, Rose L, Morris S, Powers C, Lovaglio J, Hanley PW, Scott D, Saturday G, de Wit E, Gilbert SC, Munster VJ. ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques. Nature. 2020 Oct;586(7830):578-582.

Folegatti PM, Ewer KJ, Aley PK, Angus B, Becker S, Belij-Rammerstorfer S, Bellamy D, Bibi S, Bittaye M, Clutterbuck EA, Dold C, Faust SN, Finn A, Flaxman AL, Hallis B, Heath P, Jenkin D, Lazarus R, Makinson R, Minassian AM, Pollock KM, Ramasamy M, Robinson H, Snape M, Tarrant R, Voysey M, Green C, Douglas AD, Hill AVS, Lambe T, Gilbert SC, Pollard AJ; Oxford COVID Vaccine Trial Group. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet. 2020 Aug 15;396(10249):467-478.

van Doremalen N, Bushmaker T, Morris DH, Holbrook MG, Gamble A, Williamson BN, Tamin A, Harcourt JL, Thornburg NJ, Gerber SI, Lloyd-Smith JO, de Wit E, Munster VJ. Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1. N Engl J Med. 2020 Apr 16;382(16):1564-1567.

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Major Areas of Research
  • Understanding mucosal immunity induced by respiratory virus infections and mucosal vaccination
  • Identifying correlates of protection against respiratory virus infections
  • Utilize this knowledge to design improved vaccines

John Misasi, M.D.

Specialty(s): Infectious Disease, Pediatrics
Provides direct clinical care to patients at NIH Clinical Center

Education:

M.D., 2002, SUNY Upstate Medical University, Syracuse, NY

B.S., 1996, Boston University, MA

Tracy J. Ruckwardt, Ph.D.

Subash Babu, M.B.B.S., Ph.D.

  • Host response to helminth infection and pathogenesis of helminthic disease 
  • Modulation of immune responses in co-infections and comorbidities such as tuberculosis (TB), viral infections, undernutrition, obesity, and type 2 diabetes mellitus by helminth infections
  • Immune responses, pathogenesis and biomarker discovery in pulmonary and extrapulmonary TB, and the effect of co-infections and comorbidities (diabetes mellitus. malnutrition, HIV, dengue, and SARS-CoV-2) on TB immunity and pathogenesis
  • Immune responses in and pathogenesis of SARS-CoV-2 infection, adult and pediatric COVID-19 disease, and multi-system inflammatory syndrome in children (MIS-C)
  • Immune responses to vaccination in different populations including Bacille Calmette-Guérin (BCG) vaccination in the elderly and COVID-19 vaccination in all age groups  
Section or Unit Name
Helminth Immunology Section
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Dr. Babu’s research focus is on two major thematic areas: 1) immunology of infections and 2) intersection of infectious diseases with metabolic disorders. Our group works on the immunology, pathogenesis, and epidemiology of helminth infections (particularly filariasis, strongyloidiasis, and hookworms), TB, and coexistent infectious diseases (helminths/ viruses and TB). Our group also works on the immunological and clinical outcomes of the interaction between diabetes mellitus (and other metabolic disorders) and TB, helminths (and other infectious diseases). 

Our studies have examined and described 1) the mechanisms underlying the pathogenesis of human W. bancrofti and other helminth infections; 2) the influences of helminth infections on the outcomes of metabolic disorders; 3) the correlates of protective immunity to TB, as well as its diagnostic and prognostic biomarkers; 4) the interface between diabetes mellitus/malnutrition and M. tuberculosis; 5) the immune responses in adult and pediatric COVID-19 and the pathogenesis of MIS-C; and 6) vaccine-engendered immune responses, including BCG and SARS-CoV-2 vaccines.

ICER India

Dr. Babu is the Scientific Director of the NIAID International Center for Excellence in Research (ICER) in India, a collaborative research partnership between NIAID and the Indian Ministry of Health and Family Welfare, specifically the Department of Health Research (DHR) and the Indian Council of Medical Research (ICMR). 

Clinical Studies

ICER202201 Regional Prospective Observational Research in Tuberculosis (RePORT)- Phase 2. (India, USA) Principal Investigator

ICER202101 Adult BCG revaccination induced Antibody and cTfh responses in Latent Tuberculosis individuals with or without diabetes mellitus. (India, Switzerland) Principal Investigator 

ICER202001 A cross-sectional study to estimate the influence of malnutrition, diabetes mellitus and helminth infections on biosignatures in latent tuberculosis in a South Indian population. (India, USA) NCT04526613 Principal Investigator

ICER202002 A pilot study of the effects of helminth infection and SARS-CoV-2 seropositivity on immune response and the intestinal microbiota in India. (India, USA) NCT04813328 Principal Investigator

ICER202003-02  Impact of COVID-19 on clinical manifestations, diagnosis, treatment outcome and immune response for pulmonary tuberculosis - “Associative BRICS Research in COVID-19 and Tuberculosis”. (India, Brazil, South Africa) NCT04930978 Advisor

ICER201701 Effect of Pre-diabetes on Tuberculosis severity. (India, USA) Principal Investigator

ICER201301 Host response to Infection and Treatment in Lymphatic Filarial Disease and Strongyloidiasis in India. (India, USA) NCT00342576 Principal Investigator

ICER201201 Effect of Helminth Infection on Antigen-Specific Immune Responses in Latent Tuberculosis in South India. (India, USA) NCT01547884 Principal Investigator

ICER200901 Characterization of immune responses in pulmonary TB patients who are with or without Diabetes mellitus. (India, USA) NCT01154959 Principal Investigator

ICER200701 Effect of albendazole dose and interval on Wuchereria bancrofti microfilarial clearance in India: a randomized, open label study. (India, USA) NCT00375583 Principal Investigator

ICER201501 Impact of Immune Changes in Pregnancy on Tuberculosis in HIV infected and uninfected women. (India, USA) Associate Investigator 

ICER201401 Effects of Diabetes on Tuberculosis severity. (India, USA) Associate Investigator

ICER200601 The Effect of Parasitic Worm Infections on the Immune Response to Tuberculosis Bacteria (India, USA) NCT00342017 Associate Investigator

ICER200602 Changes in HIV Viral Load in Patients Undergoing Treatment for Filariasis (India, USA) NCT00344279 Associate Investigator 

ICER India (Projects within India)
ICER202102 Characterization and Durability of COVID-19 vaccine induced immune responses in healthcare/frontline workers. NCT05049187 Principal Investigator

ICER202003-01 Impact of COVID-19 on clinical manifestations, diagnosis, treatment outcome and immune response for pulmonary tuberculosis. NCT04930978 Principal Investigator

ICER202004 Study to Evaluate the Effectiveness of the BCG vaccine in Reducing Morbidity and Mortality in Elderly individuals in COVID-19 Hotspots in India. NCT04475302 Principal Investigator

ICER202005 Role of neutralizing antibodies and inflammatory biomarkers in children with Paediatric Inflammatory Multisystem Syndrome - Temporally Associated with SARS-CoV-2 (PIMS-TS). CTRI/2021/01/030605 Principal Investigator

ICER202006 An observational study of clinical and immunological features of children with SARS-COV-2 (COVID-19) infection over a period of 12 to 16 weeks. Principal Investigator

ICER202007 Humoral and cellular immune response among recovered COVID-19 patients: A cross-sectional study, Tiruvallur district and Chennai, Tamil Nadu, India, 2020. Principal Investigator

ICER 202008 A cross sectional study of the systems immunology and viral diversity of SARS-CoV2 infection, COVID-19 disease and Multisystem Inflammatory Syndrome in children. NCT04844242 Principal Investigator

ICER201901 Systems biology and immunology of the effect of tuberculosis chemoprophylaxis in HIV infection. Principal Investigator

ICER201001  Characterization of immune responses in treatment-induced latency in pulmonary tuberculosis. NCT01154959 Principal Investigator

ICER201002 Characterization of immune responses in active tuberculosis infection. Principal Investigator

ICER201003 Characterization of Immune Responses in Tuberculosis Lymphadenitis. Principal Investigator 

ICER202103 Prevalence of cardiopulmonary vascular defects among post-COVID-19 patients using Q-SPECT/CT hybrid imaging and correlation with biomarkers for prognostication – a longitudinal study (POCOS). Associate Investigator

ICER202104 A longitudinal observational study on the impact of SARS-CoV-2 infection on Immune responses to Tuberculosis in children and adolescents (TB COVID KIDS). Associate Investigator 

ICER202009 Role of Vitamin C supplement as an adjunct to tuberculosis treatment in new smear sputum positive pulmonary tuberculosis – An exploratory trial.  Associate Investigator

ICER201702 A Phase IIB Open Label Randomized trial to evaluate the anti-bacterial activity, pharmacokinetics, safety and tolerability of Metformin when given with RIPE in adults with newly diagnosed sputum positive pulmonary tuberculosis: an 8-week study.  Associate Investigator

ICER201703 Phase IIb open label, parallel, randomized controlled trial to assess safety, tolerability, pharmacokinetics & anti-bacterial activity of high dose rifampin vs Conventional dose rifampin in standard anti-TB therapy in drug sensitive Pulmonary TB in adults. Associate Investigator 

ICER201502 Characterization of Immune Responses in Drug Resistant Pulmonary Tuberculosis. Associate Investigator

Selected Publications

Nathella PK, Moideen K, Viswanathan V, Sivakumar S, Ahamed SF, Ponnuraja C, Hissar S, Kornfeld H, Babu S. Heightened microbial translocation is a prognostic biomarker of recurrent tuberculosis. Clin Infect Dis. 2022 Mar 30:ciac236. 

Pavan Kumar N, Padmapriyadarsini C, Rajamanickam A, Marinaik SB, Nancy A, Padmanaban S, Akbar N, Murhekar M, Babu S. Effect of BCG vaccination on proinflammatory responses in elderly individuals. Sci Adv. 2021 Aug 4;7(32):eabg7181. 

Venkataraman A, Kumar NP, Hanna LE, Putlibai S, Karthick M, Rajamanikam A, Sadasivam K, Sundaram B, Babu S. Plasma biomarker profiling of PIMS-TS, COVID-19 and SARS-CoV2 seropositive children - a cross-sectional observational study from southern India. EBioMedicine. 2021 Apr;66:103317. 

Kumar NP, Kathamuthu GR, Moideen K, Banurekha VV, Nair D, Fay MP, Nutman TB, Babu S. Strongyloides stercoralis Coinfection Is Associated With Greater Disease Severity, Higher Bacterial Burden, and Elevated Plasma Matrix Metalloproteinases in Pulmonary Tuberculosis. J Infect Dis. 2020 Aug 17;222(6):1021-1026. 

Rajamanickam A, Munisankar S, Bhootra Y, Dolla C, Thiruvengadam K, Nutman TB, Babu S. Metabolic Consequences of Concomitant Strongyloides stercoralis Infection in Patients With Type 2 Diabetes Mellitus. Clin Infect Dis. 2019 Aug 1;69(4):697-704.

Anuradha R, George PJ, Pavan Kumar N, Fay MP, Kumaraswami V, Nutman TB, Babu S. Circulating microbial products and acute phase proteins as markers of pathogenesis in lymphatic filarial disease. PLoS Pathog. 2012;8(6):e1002749. 

Visit PubMed for a complete publications listing.

Additional Information
Major Areas of Research
  • Host response to helminth infection and pathogenesis of helminthic disease 
  • Modulation of immune responses in co-infections and comorbidities such as tuberculosis (TB), viral infections, undernutrition, obesity, and type 2 diabetes mellitus by helminth infections
  • Immune responses, pathogenesis and biomarker discovery in pulmonary and extrapulmonary TB, and the effect of co-infections and comorbidities (diabetes mellitus. malnutrition, HIV, dengue, and SARS-CoV-2) on TB immunity and pathogenesis
  • Immune responses in and pathogenesis of SARS-CoV-2 infection, adult and pediatric COVID-19 disease, and multi-system inflammatory syndrome in children (MIS-C)
  • Immune responses to vaccination in different populations including Bacille Calmette-Guérin (BCG) vaccination in the elderly and COVID-19 vaccination in all age groups

Subash Babu, M.B.B.S., Ph.D.

Education:

M.B.B.S., 1993, Govt. Kilpauk Medical College/ University of Madras, India

Ph.D., 1999, University of Connecticut, Storrs, CT

Headshot photograph of Dr. Subash Babu