Developing Tests to Detect Evidence of Protective Immune Responses Generated by Vaccines for Respiratory Viruses That Infect Infants, Children and the Elderly
Principal Investigator: Judy Beeler, MD
Office / Division / Lab: OVRR / DVP / LPRVD
Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract disease in young children worldwide and the most frequent reason for hospitalization of US children less than 2 years of age. Moreover, everyone is infected by this virus by 2 to 4 years of age.
RSV commonly causes repeated infections throughout life and infections in the elderly can be quite debilitating, especially in those with underlying heart and lung problems.
Currently, there are no vaccines licensed for the prevention of RSV disease in any age group. Ribavirin, the single anti-viral drug approved for treatment, is effective only if used very soon after the onset of infection. Another type of FDA-approved therapy uses a protein called a monoclonal antibody to prevent severe lung disease following infection. However, while this shows that antibodies play an important role in preventing human infection, its use is currently limited to high-risk infants during the first two years of life. Also, this preventive treatment is expensive and requires monthly injections during the time RSV circulates within communities.
Our laboratory is working to develop tests that can detect protective antibody responses. Such tests will facilitate the design and evaluation of vaccines, and therefore help to identify vaccine candidates with the greatest potential for preventing RSV disease.
In contrast to RSV, measles virus infection confers lifelong immunity and immunization with measles vaccine is thought to provide long-term protection. However, immune responses induced by measles vaccine are lower than those seen after natural infection and these responses can wane significantly over time. The measles vaccination program in the US has achieved a high level of population immunity and successfully halted the circulation of measles virus in the U.S.
However, the significant reduction in the level of measles virus circulating in the U.S. has raised a new problem. Normally, when a person who has been immunized against measles encounters the virus again, the virus may act like a "booster" to reinvigorate the initial immune response. But widespread vaccination produces "herd immunity," that significantly reduces the ability of measles virus to spread. Therefore, in the U.S. vaccinated individuals are not usually intermittently exposed to this virus again. This lack of "boosting" further contributes to the waning of immunity to measles in adults, although the direct impact of this waning immunity is not known.
In addition, waning immunity in adults has caused a decrease in the quantity of measles antibodies that are present in donated blood from vaccinated blood donors. These donations are used to make a variety of immunoglobulin products, some of which physicians use to treat individuals whose immune systems are too weak to launch a protective response to either the vaccine or to the virus itself.
Thus there is a need to monitor measles antibody levels in vaccinated populations as they age to assess the impact on herd immunity. Likewise there is a need to monitor the potency of antibody products made from vaccinated donors to ensure that their potency is sufficient to protect immunodeficient individuals.
Our research is aimed at developing new serological assays to evaluate protective antibody responses to RSV and measles.
This work includes studies to identify the cellular receptor for RSV and identify specific regions or epitopes within the virus envelope proteins responsible for binding to these receptors and mediating fusion with the cell membrane.
We use traditional neutralization and virus inhibition assays incorporating culture based systems to detect antibody responses to whole virus. We are also using immunological methods to detect antibodies elicited by infection or vaccination that bind to specific epitopes known to be important for attachment and infectivity. Antibodies that block virus attachment or abrogate virus entry can be expected to prevent virus infection and disease.
Our laboratory is also developing test methods using viruses that express reporter genes to facilitate the rapid detection of neutralizing antibody responses. We are developing a high throughput measles neutralization assay to help assess persistence of measles immunity in adults, most of whom have not benefited from periodic boosts due to the significant reduction in herd immunity in the U.S.
These assays will help to maintain the quality of immunoglobulin products used for passive immunization against measles in immunocompromised populations and permit a more rapid assessment of measles immune status in our aging vaccinated population.
Pediatr Infect Dis J 2016 Aug;35(8):e253-7
Adverse events after MMR or MMRV vaccine in infants under 9 months old.
Woo EJ, Winiecki SK, Arya D, Beeler J
J Infect Dis 2016 Apr 1;213(7):1115-23
Measles virus neutralizing antibody response, cell-mediated immunity, and IgG antibody avidity before and after a third dose of measles-mumps-rubella vaccine in young adults.
Fiebelkorn AP, Coleman LA, Belongia EA, Freeman SK, York D, Bi D, Kulkarni A, Audet S, Mercader S, McGrew M, Hickman CJ, Bellini WJ, Shivakoti R, Griffin DE, Beeler J
PLoS Pathog 2016 Apr 21;12(4):e1005554
Antigenic fingerprinting following primary RSV infection in young children identifies novel antigenic sites and reveals unlinked evolution of human antibody repertoires to fusion and attachment glycoproteins.
Fuentes S, Coyle EM, Beeler J, Golding H, Khurana S
Vaccine 2016 Mar 14;34(12):1459-64
Supplemental measles vaccine antibody response among HIV-infected and -uninfected children in Malawi after 1- and 2-dose primary measles vaccination schedules.
Fowlkes AL, Witte D, Beeler J, Audet SA, Broadhead R, Bellini WJ, Cutts F, Helfand RF
J Virol 2015 May 1;89(9):5193
Correction for kim et Al., development of an adenovirus-based respiratory syncytial virus vaccine: preclinical evaluation of efficacy, immunogenicity, and enhanced disease in a cotton rat model.
Kim E, Okada K, Beeler JA, Crim RL, Steitz J, Piedra PA, Gilbert BE, Gambotto A
J Virol 2014 May;88(9):5100-8.
Development of an adenovirus-based respiratory syncytial virus vaccine: preclinical evaluation of efficacy, immunogenicity, and enhanced disease in a cotton rat model.
Kim E, Okada K, Beeler JA, Crim RL, Piedra PA, Gilbert BE, Gambotto A
Clin Vaccine Immunol 2014 Mar;21(3):383-90
Development of a luciferase immunoprecipitation system assay to detect IgG antibodies against human respiratory syncytial virus nucleoprotein.
Kumari S, Crim RL, Kulkarni A, Audet SA, Mdluli T, Murata H, Beeler JA
Pediatr Infect Dis J 2013 Oct;32(10):1156-7
Mumps vaccines: do we need a new one?
Rubin S, Beeler J
Vaccine 2013 Aug 20;31(37):3987-94
Development of a simple, rapid, sensitive, high-throughput luciferase reporter based microneutralization test for measurement of virus neutralizing antibodies following respiratory syncytial virus vaccination and infection.
Fuentes S, Crim RL, Beeler J, Teng MN, Golding H, Khurana S
Virol J 2013 Jun 15;10:195
A neutralization assay for respiratory syncytial virus using a quantitative PCR-based endpoint assessment.
Varada JC, Teferedegne B, Crim RL, Mdluli T, Audet S, Peden K, Beeler J, Murata H
J Infect Dis 2013 Feb;207(4):574-82
Measles humoral and cell-mediated immunity in children aged 5-10 years after primary measles immunization administered at 6 or 9 months of age.
Gans HA, Yasukawa LL, Sung P, Sullivan B, Dehovitz R, Audet S, Beeler J, Arvin AM
Microb Pathog 2012 Dec 13;55C:9-15
Influenza and respiratory syncytial virus (RSV) vaccines for infants: safety, immunogenicity, and efficacy.
Beeler JA, Eichelberger MC
J Infect Dis 2012 Aug;206(4):512-522
Immunogenicity, Immunologic Memory, and Safety Following Measles Revaccination in HIV-Infected Children Receiving Highly Active Antiretroviral Therapy.
Abzug MJ, Qin M, Levin MJ, Fenton T, Beeler JA, Bellini WJ, Audet S, Sowers SB, Borkowsky W, Nachman SA, Pelton SI, Rosenblatt HM, the International Maternal Pediatric Adolescent AIDS Clinical Trials Group P1024 and P1061s Protocol Teams
J Infect Dis 2011 Aug;204(3):426-32
Increasing the time of exposure to aerosol measles vaccine elicits an immune response equivalent to that seen in 9-month-old mexican children given the same dose subcutaneously.
Wong-Chew RM, García-León ML, Espinosa-Torres Torrija B, Hernández-Pérez B, Cardiel-Marmolejo LE, Beeler JA, Audet S, Santos-Preciado JI
J Infect Dis 2011 Jul;204 Suppl 1:S179-89
Safety and immunogenicity of early measles vaccination in children born to HIV-infected mothers in the United States: results of Pediatric AIDS Clinical Trials Group (PACTG) protocol 225.
Chandwani S, Beeler J, Li H, Audet S, Smith B, Moye J, Nalin D, Krasinski K; PACTG 225 Study Team
J Infect Dis 2011 Jul;204 Suppl 1:S549-58
Laboratory characterization of measles virus infection in previously vaccinated and unvaccinated individuals.
Hickman CJ, Hyde TB, Sowers SB, Mercader S, McGrew M, Williams NJ, Beeler JA, Audet S, Kiehl B, Nandy R, Tamin A, Bellini WJ
J Infect Dis 2011 Jul;204 Suppl 1:S149-57
Persistence of vaccine-induced measles antibody beyond age 12 months: a comparison of response to one and two doses of Edmonston-Zagreb measles vaccine among HIV-infected and uninfected children in Malawi.
Fowlkes A, Witte D, Beeler J, Audet S, Garcia P, Curns A, Yang C, Fudzulani R, Broadhead R, Bellini WJ, Cutts F, Helfand RF
Vaccine 2011 Feb 1;29(6):1319-23
Thrombocytopenia after vaccination: case reports to the US Vaccine Adverse Event Reporting System, 1990-2008.
Woo EJ, Wise RP, Menschik D, Shadomy SV, Iskander J, Beeler J, Varricchio FA, Ball R
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