Protecting Kids: Developing a Vaccine for Respiratory Syncytial Virus

Baby at the Doctor's OfficeVaccines are one of biomedicine’s most powerful and successful tools for protecting against infectious diseases. While we currently have safe and effective vaccines to prevent measles, mumps, and a great many other common childhood diseases, we still lack a vaccine to guard against respiratory syncytial virus (RSV)—a leading cause of pneumonia among infants and young children.

Each year, more than 2 million U.S. children under the age of 5 require medical care for pneumonia and other potentially life-threatening lower respiratory infections caused by RSV [1,2]. Worldwide, the situation is even worse, with more than 30 million infections estimated to occur annually, most among kids in developing countries, where as many as 200,000 deaths may result [3]. So, I’m pleased to report some significant progress in biomedical research’s long battle against RSV: encouraging early results from a clinical trial of an experimental vaccine specifically designed to outwit the virus.

In a study published in Science Translational Medicine [4], an NIH-supported team administered nose drops containing either the new experimental RSV vaccine or a placebo to 60 volunteers, 45 of whom were children under the age of 5. The researchers found that children who received the new vaccine mounted a stronger immune response against RSV than seen in previous tests of another experimental vaccine. What’s more, the study provided some very preliminary evidence that the new vaccine may confer protection against RSV in real-world settings during the fall and winter—the prime time for RSV infection in the United States.

The new vaccine, which was created through a Cooperative Research and Development Agreement between NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and MedImmune, Gaithersburg, MD, consists of a live, weakened virus. When developing vaccines that use live weakened viruses, the key is to find the right balance between retaining a virus’ ability to spur an immune response and curtailing its ability to cause illness. Scientists appear to have hit this sweet spot with the latest RSV vaccine, which was designed by using the tools of molecular biology to exploit knowledge gained through basic virology research.

Back in the 1980s, NIAID’s Peter Collins, who is a co-author of the latest study, and an NIAID colleague, discovered an RSV gene called M2-2 [5]. They learned that this gene acts as a regulatory switch between the transcription and replication of the virus’s genetic material. Researchers then used genetic engineering technology to delete the M2-2 gene. When compared to a regular, “wild-type” virus, the genetically engineered virus produced larger amounts of protein recognizable by the human immune system, increasing the odds it would make an effective vaccine. But importantly, it also made fewer new copies of itself, reducing the likelihood that it would make humans sick. To those on the NIAID team, this live virus, weakened in very specific ways through genetic engineering, looked like an ideal candidate for an RSV vaccine and efforts were begun to lay the groundwork for testing in humans.

The result was a new experimental vaccine, called RSV MEDI ΔM2-2, which entered a Phase 1 clinical trial in September 2011, carried out by Ruth Karron and her colleagues at the Johns Hopkins Bloomberg School of Public Health, Baltimore, and the Seattle Children’s Research Institute. To ensure the safety of the vaccine, it was first administered to a group of 15 adults before being given to 10 children who had already had an RSV infection, followed by 20 infants and children who had no signs of previous RSV exposure. Fifteen other children in the study received a placebo.

All but one of the 20 children in the no-previous exposure group developed neutralizing antibodies, which are predictive of protection against natural infection. Follow up of these children also revealed that during the fall and winter after they received the vaccine, several experienced a rise in RSV antibodies without getting sick. This suggests that the vaccine had a protective effect during the high season for RSV infection.

Only one child who received the vaccine developed any signs of RSV illness during the follow-up period. Further research showed the youngster had become infected with a second strain of RSV that was not contained in the vaccine. This indicates that a broadly protective RSV vaccine may need to include this strain of RSV as well.

The latest results are a product of NIAID’s sustained efforts, begun more than 50 years ago, to understand the biology of RSV infection and to develop more effective ways to treat and prevent it. The work has been arduous and slow, in part because RSV is difficult to grow and study in the lab. Great care is also needed to conduct clinical trials in babies and young children, who are at the greatest risk of RSV infection and most in need of a vaccine. Despite these and many other challenges, NIH remains committed to pursuing a safe and effective RSV vaccine because of its tremendous potential to protect children’s health, both here in the United States and around the globe.

References:

[1] Respiratory Syncytial Virus Infection (RSV), Trends and Surveillance, May 5, 2015 (Centers for Disease Control and Prevention)

[2] The burden of respiratory syncytial virus infection in young children. Hall CB, Weinberg GA, Iwane MK, Blumkin AK, Edwards KM, Staat MA, Auinger P, Griffin MR, Poehling KA, Erdman D, Grijalva CG, Zhu Y, Szilagyi P. N Engl J Med. 2009 Feb 5;360(6):588-598.

[3] Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Nair H, Nokes DJ, Gessner BD, Dherani M, Madhi SA, Singleton RJ, O’Brien KL, Roca A, Wright PF, Bruce N, Chandran A, Theodoratou E, Sutanto A, Sedyaningsih ER, Ngama M, Munywoki PK, Kartasasmita C, Simões EAF, Rudan I, Weber MW, Campbell H Lancet. 2010 May 1;375(9725):1545–1555.

[4] A gene deletion that up-regulates viral gene expression yields an attenuated RSV vaccine with improved antibody responses in children. Karron RA, Luongo C, Thumar B, Loehr KM, Englund JA, Collins PL, Buchholz UJ. Sci Transl Med. 2015 Nov 4;7(312):312ra175.

[5] The envelope-associated 22K protein of human respiratory syncytial virus: nucleotide sequence of the mRNA and a related polytranscript. Collins PL, Wertz GW. J Virol.1985 Apr;54(1):65–71.

Links:

Respiratory Syncytial Virus (RSV) (National Institute of Allergy and Infectious Diseases/NIH)

Vaccines (National Institute of Allergy and Infectious Diseases/NIH)

Evaluating the Safety and Immune Response to a Respiratory Syncytial Virus (RSV) Vaccine in Adults, RSV-Seropositive Children, and RSV-Seronegative Infants and Children (ClinicalTrials.gov)

Ruth Karron (Johns Hopkins Bloomberg School of Public Health, Baltimore)

Peter Collins Lab (National Institute of Allergy and Infectious Diseases/NIH)

NIH Support: National Institute of Allergy and Infectious Diseases; National Center for Advancing Translational Sciences