Developing Tests to Detect Biomarkers of Vaccine Efficacy to Respiratory Viruses that Infect Infants, Children and the Elderly

Principal Investigator: Judy Beeler, MD
Office / Division / Lab: OVRR / DVP / LPRVD

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Overview

Public Health Issue: Respiratory syncytial virus is the most common infectious cause of wheezing and pneumonia in young children worldwide and is the most frequent reason for hospitalization in US children less than 2years old. Severe infections early in life may predispose to asthma later and everyone is infected by 2 to 4 years of age. Repeated infections throughout life are typical with each subsequent infection usually less severe than the previous one. In addition, RSV lung infection in the elderly can be debilitating especially in those with underlying heart or lung disease. Currently, there are no vaccines licensed to prevent RSV infection. Ribavirin, the single anti-viral drug approved for treatment, is only effective if used very soon after the onset of infection. An FDA approved humanized anti-RSV-F monoclonal antibody prevents severe RSV disease in high-risk infants, demonstrating that antibodies can play an important role in preventing or ameliorating human infection. Tests that can detect protective antibody responses will help in the design and evaluation of vaccines with the potential for preventing this disease. In contrast, measles virus infection confers lifelong immunity and immunization is thought to provide long term protection. However, recent studies have indicated that vaccine-induced immunity may wane significantly over time. The direct impact of waning immunity in adults is not known. However, as a secondary effect of low levels of measles antibody in adults we have seen a decrease in measles antibody potency in immunoglobulin products derived from their plasma. Thus there is a need to monitor measles antibody levels in vaccinated populations as they age to determine if there is an impact on herd immunity and, likewise, there is a need to monitor measles antibody potency in immunoglobulin products to assure that there is sufficient measles antibody to provide reliable passive protection for immunodeficient populations.

Regulatory Contribution: It is important to be able to detect immune responses specifically associated with protection. This will facilitate vaccine development, as it will help to select vaccine candidates based on testing in animals and advance those with the protective responses into human clinical trials. Serological correlates of protection also facilitate human clinical testing as they help to verify susceptibility of the target population so that a true measure of vaccine effectiveness can be made. In some cases these tests may actually decrease the numbers of children required to demonstrate efficacy. The measles plaque reduction neutralization test has long been used to measure serum neutralizing antibody however, it is technically challenging and tedious to perform. Assessing vaccine induced immunity and monitoring measles antibody potency in immunoglobulin products would be helped by the development of an automated high-throughput assay to detect measles neutralizing antibody levels.

Research Approach: This research program is designed to develop new tests to evaluate antibody responses to RSV and measles. These efforts include studies to identify the cellular receptor(s) for RSV as well as identify specific regions of the virus envelope proteins responsible for binding to these receptors. Traditional neutralization and virus inhibition assays using tissue culture based systems will be used as well as immunological methods to detect antibodies elicited by infection or vaccination that bind to the virus peptides identified as important for attachment and infectivity. Antibodies that can block virus attachment and/or entry can be expected to prevent infection and disease. Test methods will also be developed using viruses expressing reporter genes to facilitate the rapid detection of neutralizing antibody responses.

Mission Relevance & Outcomes: These studies will provide tools for supporting the development of effective RSV vaccines and help maintain the quality of immunoglobulin products used for passive immunization against respiratory viruses such as measles.

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Publications

Vaccine 2008 Sep 8;26(38):4877-8
ELISA underestimates measles antibody seroprevalence in US military recruits.
Mancuso JD, Krauss MR, Audet S, Beeler JA

J Infect Dis 2008 Aug 15;198(4):508-515
Antibody Induced by Immunization with the Jeryl Lynn Mumps Vaccine Strain Effectively Neutralizes a Heterologous Wild-Type Mumps Virus Associated with a Large Outbreak.
Rubin SA, Qi L, Audet SA, Sullivan B, Carbone KM, Bellini WJ, Rota PA, Sirota L, Beeler J

Clin Infect Dis 2007 Dec 1;45(11):1417-24
The influence of HIV-1 exposure and infection on levels of passively acquired antibodies to measles virus in Zambian infants.
Scott S, Moss WJ, Cousens S, Beeler JA, Audet SA, Mugala N, Quinn TC, Griffin DE, Cutts FT

Vaccine 2007 Dec 21;26(1):59-66
Plaque reduction neutralization test for measles antibodies: Description of a standardised laboratory method for use in immunogenicity studies of aerosol vaccination.
Cohen BJ, Audet S, Andrews N, Beeler J, WHO working group on measles plaque reduction neutralization test

Vaccine 2007 Aug 1;25(31):5717-24
Thrombocytopenia: Case definition and guidelines for collection, analysis, and presentation of immunization safety data.
Wise RP, Bonhoeffer J, Beeler J, Donato H, Downie P, Matthews D, Pool V, Riise-Bergsaker M, Tapiainen T, Varricchio F, The Brighton Collaboration Thrombocytopenia Working Group

Arch Virol 2007 Aug;152(8):1425-34
Genetic variability of group A and B human respiratory syncytial viruses isolated from 3 provinces in China.
Zhang Y, Xu W, Shen K, Xie Z, Sun L, Lu Q, Liu C, Liang G, Beeler JA, Anderson LJ

J Infect Dis 2007 Aug 1;196(3):347-55
Immunogenicity of Standard-Titer Measles Vaccinein HIV-1-Infected and Uninfected Zambian Children: An Observational Study.
Moss WJ, Scott S, Mugala N, Ndhlovu Z, Beeler JA, Audet SA, Ngala M, Mwangala S, Nkonga-Mwangilwa C, Ryon JJ, Monze M, Kasolo F, Quinn TC, Cousens S, Griffin DE, Cutts FT

Arch Pediatr Adolesc Med 2007 Mar;161(3):294-301
Persistence of Measles Antibodies After 2 Doses of Measles Vaccine in a Postelimination Environment.
Lebaron CW, Beeler J, Sullivan BJ, Forghani B, Bi D, Beck C, Audet S, Gargiullo P

Pediatrics 2007 Mar;119(3):e574-9
Measles-mumps-rubella and varicella vaccine responses in extremely preterm infants.
D'Angio CT, Boohene PA, Mowrer A, Audet S, Menegus MA, Schmid DS, Beeler JA

J Virol 2007 Jan;81(1):261-71
Identification of linear heparin binding peptides derived from the human respiratory syncytial virus fusion glycoprotein that inhibit infectivity.
Crim RL, Audet SA, Feldman SA, Mostowski HS, Beeler JA

J Infect Dis 2006 Sep 15;194(6):781-9
Measles-virus-neutralizing antibodies in intravenous immunoglobulins.
Audet S, Virata-Theimer ML, Beeler JA, Scott DE, Frazier DJ, Mikolajczyk MG, Eller N, Chen FM, Yu MY

J Virol 2006 May;80(10):5032-40
Alpha and lambda interferon together mediate suppression of CD4 T cells induced by respiratory syncytial virus.
Chi B, Dickensheets HL, Spann KM, Alston MA, Luongo C, Dumoutier L, Huang J, Renauld JC, Kotenko SV, Roederer M, Beeler JA, Donnelly RP, Collins PL, Rabin RL

Vaccine 2006 Jan 30;24(5):683-90
Immunogenicity of aerosol measles vaccine given as the primary measles immunization to nine-month-old Mexican children.
Wong-Chew RM, Islas-Romero R, Garcia-Garcia MD, Beeler JA, Audet S, Santos-Preciado JI, Gans H, Lew-Yasukawa L, Maldonado YA, Arvin AM, Valdespino-Gomez JL

Vaccine 2005 May 9;23(25):3247-55
Follow-up of infants given measles vaccine at 6 months of age: antibody and CMI responses to MMRII at 15 months of age and antibody levels at 27 months of age.
Carson MM, Spady DW, Beeler JA, Krezolek MP, Audet S, Pabst HF

J Infect Dis 2004 Jul 1;190(1):83-90
Humoral and cell-mediated immune responses to an early 2-dose measles vaccination regimen in the United States.
Gans HA, Yasukawa LL, Alderson A, Rinki M, DeHovitz R, Beeler J, Audet S, Maldonado Y, Arvin AM

J Virol 2004 May 15;78(10):5015-5022
RhoA-Derived Peptide Dimers Share Mechanistic Properties with Other Polyanionic Inhibitors of Respiratory Syncytial Virus (RSV), Including Disruption of Viral Attachment and Dependence on RSV G.
Budge PJ, Li Y, Beeler JA, Graham BS

J Infect Dis 2004 Jan 15;189(2):254-7
Induction of cellular and humoral immunity after aerosol or subcutaneous administration of Edmonston-Zagreb measles vaccine as a primary dose to 12-month-old children.
Wong-Chew RM, Islas-Romero R, Garcia-Garcia Mde L, Beeler JA, Audet S, Santos-Preciado JI, Gans H, Lew-Yasukawa L, Maldonado YA, Arvin AM, Valdespino-Gomez JL