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.
- Vaccine 2020 Jan 10;38(2):101-6
Summary of the Vaccines and Related Biological Products Advisory Committee meeting held to consider evaluation of vaccine candidates for the prevention of respiratory syncytial virus disease in RSV-naive infants.
Browne SK, Beeler JA, Roberts JN
- J Pediatric Infect Dis Soc 2019 Oct 23 [Epub ahead of print]
Measles maternal antibodies with low avidity do not interfere with the establishment of robust quantity and quality antibody responses after the primary dose of measles, mumps, and rubella vaccine administered at 12-months of age.
Collins CA, Gelinas L, Yasukawa LL, Audet S, Abu-Raya B, Turvey SE, Beeler JA, Kollmann TR, Gans HA
- PLoS One 2019 Aug 15;14(8):e0220780
Development of a high-throughput assay to measure measles neutralizing antibodies.
Alvarado-Facundo E, Audet S, Moss WJ, Beeler JA
- PLoS One 2019 Apr 15;14(4):e0215321
The effect of respiratory viruses on immunogenicity and protection induced by a candidate universal influenza vaccine in mice.
Rowell J, Lo CY, Price GE, Misplon JA, Crim RL, Jayanti P, Beeler J, Epstein SL
- Vaccines 2019 Feb 1;7(1):16
Development of luciferase immunoprecipitation systems (LIPS) assay to detect IgG antibodies against human respiratory syncytial virus G-Glycoprotein.
Crim RL, Kumari S, Jayanti P, Audet S, Kulkarni A, Beeler J
- Vaccine 2016 Sep 22;34(41):4843-9
Challenges and opportunities in RSV vaccine development: meeting report from FDA/NIH workshop.
Roberts JN, Graham BS, Karron RA, Munoz FM, Falsey AR, Anderson LJ, Marshall V, Kim S, Beeler JA
- 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