RSV vaccine development about to enter ‘golden age’

No vaccine is currently approved for respiratory syncytial virus, or RSV. However, for the first time in decades, numerous vaccines are in the pipeline — particulary in the past 5 years. The increase in activity followed a long delay after a catastrophic vaccine failure in the 1960s killed two infants.

An RSV “snapshot” released by PATH, an organization that brings together public- and private-sector partners to develop vaccines, shows dozens of investigational trials for RSV vaccines and monoclonal antibodies.

Source: Dan Smith/Nationwide Children’s Hospital

“The advances in the past 5 years have been exponential,” Octavio Ramilo, MD, chief of the division of infectious diseases at Nationwide Children’s Hospital, said in an interview with Infectious Diseases in Children. “We probably have advanced more in the past 5 years than the previous 25 years.”

Infectious Diseases in Children spoke with Ramilo and other experts about some of the historical challenges of RSV vaccine development, the vaccines in the pipeline they are most excited about and how close researchers are to bringing a vaccine to market.

History and symptoms

RSV is the leading cause of serious lower respiratory diseases in young children worldwide, according to researchers. The virus is estimated to cause up to 160,000 deaths annually across the globe, and most of these deaths occur among young children. About 3.4 million children aged 5 years and younger worldwide are hospitalized each year with severe RSV. In the United States alone, 75,000 to 125,000 children aged 2 years and younger are hospitalized annually, according to the NIH.

The NIH cites RSV as the single most important cause of severe lower respiratory tract infection in young children, frequently causing winter outbreaks of acute respiratory disease. The most common clinical manifestations are upper respiratory tract infections and bronchiolitis, and complications include otitis media and pneumonia.

Among those at highest risk for severe disease are premature infants, young children with congenital heart or chronic lung disease and young children with compromised immune systems, as well as adults with compromised immune systems and older adults, according to the CDC.

Although RSV is considered a cold virus, it goes further into the airways in small children and those who are immunocompromised. “These children have low blood levels of oxygen, and they have to be admitted to the hospital for respiratory support,” C. Buddy Creech, MD, MPH, associate professor of pediatrics in the division of pediatric infectious diseases and director of the Vanderbilt Vaccine Research Program, told Infectious Diseases in Children. “Sometimes they can’t eat or drink because they are so focused on trying to breathe, so they can become dehydrated.”

The RSV virus was discovered in 1956 as the chimpanzee coryza agent, and it was subsequently associated with bronchiolitis in children, according to Barney S. Graham, MD, PhD, deputy director of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases (NIAID), part of the NIH.

In a commentary published in Current Opinion in Virology, Graham noted that RSV has multiple mechanisms of evading immunity, including anatomical evasion, conformational evasion of neutralizing antibody and direct modulation of immune function.

Graham explained to Infectious Diseases in Children that anatomical evasion is how RSV infects the superficial ciliated cells in the airway while not being systemic inside the body, and conformational evasion involves the virus’ F protein flipping from one neutralization-sensitive conformation to another, less sensitive form. Direct modulation of immune function includes the NS1 and NS2 proteins interfering with interferon, an innate antiviral defense mechanism, whereas the G protein can bind dendritic cells and affect their function.

“RSV is the HPV of the respiratory tract,” Graham wrote in his commentary. “It infects the superficial epithelium of the airway and is even more superficial and protected from systemic immunity than HPV because its tropism does not include basal epithelium. ... The virus evades much of the systemic immune mechanisms by residing primarily outside the body.”

The immune response from RSV is very different from that of other common viruses, Ramilo said. For instance, if you are infected with measles, you develop immunity for life. But if you develop RSV, you can acquire it again because there is no immune memory developed against the virus.

The process of understanding how to develop protection against RSV has been very slow, Ramilo said, but he is much more optimistic than he was just a few years ago.

Graham noted that there are multiple strategies for developing RSV vaccines. One approach is to use the F protein of the virus. The vaccine would be given intramuscularly to pregnant women, with the hope that it would boost their antibody response, and that antibody would be transferred to the baby. It could also be used in at-risk elderly patients.

A second approach would be to attack the surfaces on the RSV F protein in infants at birth using a monoclonal antibody — referred to as “passive immunity” — but this is not technically a vaccine. Sanofi is currently using this approach to develop a treatment similar to Synagis (palivizumab, AstraZeneca) — a monoclonal antibody recommended exclusively for high-risk children to protect against RSV. However, according to Graham, the Sanofi antibody is much more potent, and it would be given to all infants, not just those at high risk.

The third approach is a live-attenuated virus vaccine, or gene-based delivery, which would be given intranasally to young children. Multiple pharmaceutical companies are pursuing this method of vaccination, and researchers are also looking to use Sanofi’s investigational monoclonal antibody in conjunction with a vaccine given to the child later, Graham said.

Vaccine failure in the 1960s

Progress on a vaccine for RSV almost came to a halt after an investigational vaccine failed in 1966. A formalin-inactivated RSV vaccine, which was being tested in the U.S., not only failed to protect children, but many infants experienced worse symptoms than usual, requiring hospitalization. Two toddlers died with enhanced disease symptoms, according to researchers.

“We tried an RSV vaccine in the 1960s, and things went sideways,” said Creech, who is also an Infectious Diseases in Children Editorial Board member.

In the absence of a vaccine, the only option pediatricians currently have is palivizumab.

“That is what we’ve done for RSV for years, and it is expensive,” Creech said. “And there’s no way that it will work as well as giving a vaccine.”

Creech emphasized that not only are researchers looking for an effective vaccine, but they are trying to determine who should get it.

“By the age of 2, almost every child in the U.S. is infected with RSV,” he said.

Because RSV does not induce long-term immunity, subsequent infections cannot be prevented, Creech said.

Accordingly, Graham said, the vaccine has to induce better long-term immunity than the natural infection. He explained that a vaccine for young children would prevent lower airway disease and severe illness in children.

RSV vaccines in the pipeline

Creech discussed a new clinical trial by NIAID of an investigational vaccine designed to protect against RSV. The phase 1 study has enrolled a small group of healthy adult volunteers to examine the safety of an experimental intranasal vaccine and its ability to induce an immune response. The study is being conducted at the Cincinnati Children’s Hospital Medical Center, one of the NIAID-funded Vaccine and Treatment Evaluation Units.

The vaccine combines a portion of RSV with Sendai virus, which is found in mice. The vaccine is administered through a drip in the nose. The hope is that the Sendai virus will provide protection against parainfluenza (a close relative to Sendai) infections and the F protein will provide protection against RSV.

Creech explained the thought behind using the nose drip: “You don’t get RSV by getting a needle in your arm,” he said. “You get RSV by it landing in your nose. If we can make your immune system respond to the virus the way it might if it were found in your nose, we may get a better response.”

David I. Bernstein, MD, MA, director of the division of infectious diseases at Cincinnati Children’s Hospital Medical Center and one of the investigators in the vaccine study, said Sendai is “the backbone of the vaccine.”

“Sendai grows well in mice and is a pathogen in mice but, although it can replicate in humans, it is not a pathogen in people, so we were confident that people would not get sick from Sendai virus,” Bernstein told Infectious Diseases in Children.

The vaccine also combines the RSV protein that causes the virion membrane to fuse with the target cell — the F protein — into the Sendai virus.

“The goal of the study is to demonstrate that the vaccine is safe and that when the vaccine recipient’s immune system sees the RSV F protein, it will develop a strong antibody response against it,” said Alan Embry, PhD, chief of the Respiratory Diseases Branch at the NIAID. “Ultimately, it is hoped that the generation of those antibodies will be enough to prevent infection in people who later become exposed to the virus.”

In general, with RSV vaccines that are intended for the pediatric population, the first step is to perform a safety study in healthy adults who have previously been exposed to the virus. The next step is to study the vaccine in children, Embry said.

Cincinnati Children’s Hospital has enrolled 20 adults, and all but one has completed the study. Bernstein expects it will be at least 6 months to a year after the study is completed in adults before any trials will begin with children, but researchers are hopeful the vaccine will work.

He said they learned from the failed vaccine in the 1960s, which was a killed vaccine.

“We think that it’s better to give a live, weakened virus,” he said. “It’s one of the reasons that it’s 2018 and we don’t have an RSV vaccine,” he said. “We are more cautious with RSV than other vaccines; for example, although rotavirus was discovered after RSV, we have had a vaccine for 12 years.”

As a live-attenuated virus, the hope is that the vaccine will last a lifetime, Bernstein said, but a booster dose may be needed for the elderly, who may also get serious RSV disease.

“There is a critical need to develop a safe and effective vaccine to prevent disease caused by RSV, so it is important that we support basic and clinical research, including this particular trial,” Embry said.

GlaxoSmithKline (GSK) and Janssen are also among the companies racing to develop a vaccine for RSV.

A spokeswoman for GSK told Infectious Diseases in Children that “GSK has an active research program to develop an RSV vaccine” — including an approach to help prevent disease through maternal vaccination.

Janssen is conducting a phase 1/2 study investigating the safety and immunogenicity of a vaccine in RSV-seropositive children aged 12 to 24 months.

“We are currently developing an investigational adenovirus type 26-based vaccine expressing the RSV F protein stabilized in the prefusion conformation,” Benoit Callendret, PhD, scientific director and compound development team leader for RSV at Janssen, told Infectious Diseases in Children. “This vaccine candidate is being studied in both pediatric and adult populations. In pediatrics, we aim to develop a vaccine for use in early infancy together with other routine childhood vaccines.”

Callendret said the development of an RSV vaccine for infants is complicated by the history of vaccine-enhanced respiratory disease (ERD) that was observed during the deadly trial in the 1960s.

“Our investigational approach is designed to avoid ERD,” he said.

Ramilo told Infectious Diseases in Children that he was particularly optimistic about a Novavax vaccine called ResVax being developed for pregnant women, in which the antibody would be passed through the placenta to the baby. Results of a phase 3 trial were presented at the World Vaccine Congress in April. A data safety monitoring board reported no safety concerns in the trial.

If the vaccine is successful, the babies will have antibodies in the first 3 months of life, and physicians will be able to immunize the infants when they are slightly older, around age 6 months, Ramilo said.

“The first approved vaccine will probably be a maternal vaccine,” Ramilo said. “If we can decrease the hospitalizations in these young babies, it will have a huge impact.”

ResVax is a recombinant RSV fusion protein nanoparticle vaccine. As the only vaccine currently in phase 3 development, ResVax “represents the first potential opportunity to prevent RSV disease in infants,” according to Gregory M. Glenn, MD, president of research and development at Novavax. “The lack of effective treatments for RSV necessitates a focus on protecting infants from birth through the first months of their life,” Glenn told Infectious Diseases in Children. “Maternal immunization offers the best method of protection from RSV disease in infants under 6 months of age.”

Novavax has completed enrollment of 4,636 women in its global trial of the vaccine, which is administered by intramuscular injection in the third trimester.

An informational analysis conducted earlier this year by Novavax showed that the vaccine had a calculated efficacy of 45% to 100%, Glenn said.

“We expect to report results from our final analysis in the first quarter of 2019, and that these results will support our filing of a biologics license application with the FDA and a marketing authorization application with the European Medicines Agency by the first quarter of 2020.” he said.

Glenn added that the FDA granted the vaccine a fast-track designation, which could accelerate the standard FDA review time by 4 months.

Although no vaccines have been submitted for approval yet, Ramilo said he expects that to change in the next 3 years.

“I suspect we will have different types of vaccines for different populations or age groups — children, pregnant women or the elderly,” Ramilo said

Looking forward

Experts emphasized that much more work is needed before a vaccine is available in the pediatricians’ office.

“In general, there have been a number of recent advances in the field that have stimulated new development, but while we are optimistic, clearly we think that more research is needed to understand the host response to infection and the requirement of a protective vaccine,” Embry said.

Graham said there are about 120 million babies born each year, so an RSV vaccine would not be available worldwide initially.

“But there are a lot of people working toward how all 120 million babies can be protected by the RSV vaccine,” he said.

Graham said he believes an RSV vaccine will first be available in the U.S.

“There’s a lot of effort going into how to make these types of vaccines to see if they are successful and available to larger parts of the world,” he added.

Graham estimated that it will be another 5 to 10 years before a vaccine’s efficacy is demonstrated and a product is finally approved by the FDA.

Despite the work that remains, multiple sources told Infectious Diseases in Children that, overall, the future of RSV vaccine development looks bright.

“We are about to begin the golden age of RSV vaccines,” Creech said. – by Bruce Thiel

• References:
• CDC, RSV Transmission. https://www.cdc.gov/rsv/about/transmission.html. Accessed August 21, 2018.
• Graham BS. Curr Opin Virol. 2017;doi:10.1016/j.conviro.2017.03.012.
• Kim S. The Jordan Report: Accelerated development of vaccines 2012. https://www.niaid.nih.gov/sites/default/files/jordanreport2012.pdf. Accessed August 30, 2018.
• Mullard, A. Nature. 2008;doi:10.1038/news.2008.1302.
• Nair H, et al. Lancet. 2010;doi:10.1016/S0140-6736(10)60206-1.
• Neuzil KM. Clin Vaccine Immunol. 2016;doi:10.1128/CVI.00037-16.
• NIH. Respiratory Syncytial Virus (RSV). https://www.niaid.nih.gov/diseases-conditions/respiratory-syncytial-virus-rsv. Accessed August 21, 2018.
• Novavax. RSV F Nanoparticle Vaccine: Infants via Maternal Immunization. Presented at: World Vaccine Congress; April 3-5, 2018; Washington, D.C.
• Path. RSV Vaccine and mAB Snapshot. https://www.path.org/resources/rsv-vaccine-and-mab-snapshot/. Accessed August 16, 2018.

• For more information:
• David I. Bernstein, MD, MA, can be reached at David.Bernstein@cchmc.org.
• Benoit Callendret, PhD, can be reached at kbuckle8@its.jnj.com.
• C. Buddy Creech, MD, MPH, can be reached at Buddy.creech@vumc.org.
• Alan Embry, PhD, can be reached at embrya@niaid.nih.gov.
• Gregory M. Glenn, MD, can be reached at MikeBeyer@sambrown.com.
• Barney S. Graham, MD, PhD, can be reached at bgraham@mail.nih.gov.
• Octavio Ramilo, MD, can be reached at Octavio.Ramilo@nationwidechildrens.org.

Disclosures: Callendret reports being a full-time employee of Janssen Vaccines & Prevention B.V. Creech reports receiving funding from the NIH for work on assays related to RSV immunity. Glenn is employed by and a shareholder of Novavax. Graham reports owning intellectual property on aspects of RSV biology and vaccine development. Bernstein, Embry and Ramilo report no relevant financial disclosures.