Why the success of Pfizer’s RSV vaccine is a big deal, decades in the making

Why the success of Pfizer’s RSV vaccine is a big deal, decades in the making

    An intensive care nurse cares for a patient with respiratory syncytial virus (RSV) who is on ventilation in the pediatric intensive care unit of the Olga Clinic Stuttgart Hospital in Germany.
Increase / An intensive care nurse cares for a patient with respiratory syncytial virus (RSV) who is on ventilation in the pediatric intensive care unit of the Olga Clinic Stuttgart Hospital in Germany.

As an unusually large and early seasonal surge of RSV cases overwhelmed children’s hospitals across the country, pharmaceutical giant Pfizer offered a glimmer of hope Tuesday in the form of top results from a phase three clinical trial.

An experimental RSV vaccine given to pregnant women was 82 percent effective in preventing severe lower respiratory tract disease associated with RSV in the first three months of a newborn’s life. It was 69 percent effective in the first six months, Pfizer said.

“We are thrilled with these data because this is the first vaccine to be tested as proven to help protect infants from severe respiratory disease caused by RSV immediately after birth,” said Annaliesa Anderson, Pfizer’s chief scientific officer.

The company said it plans to apply for regulatory approval from the Food and Drug Administration by the end of the year, which could mean the vaccine could be available in time for next year’s RSV season.

The announcement is promising, but there are also reasons for caution. The company released only the top results in a press release, for one thing. The data will need to undergo a more detailed external review. Pfizer also noted that the vaccine failed to meet the second of the trial’s two primary objectives, which was to meet pre-specified statistical criteria for efficacy against it is not difficult RSV-related lower respiratory tract disease – although the company says some efficacy was clinically meaningful.

Still, there’s reason to be excited about Tuesday’s news, which follows decades of struggle by researchers trying to fight RSV. These include the disastrous vaccine trial in the 1960s, which led to the development of vaccinated children more severe illness from RSV infection and led to the tragic death of two infants.

An often overlooked virus

It may seem newly familiar, but RSV—or respiratory syncytial (syn-SISH-uhl) virus—is a common, seasonal virus that has long posed a serious risk to infants and young children. Almost everyone is infected in childhood, and most experience only a mild respiratory illness. But for a small proportion of children, especially those under the age of 5, it can become life-threatening. RSV sends around 3.6 million to the hospital every year worldwide and kills over 100,000 children under the age of 5 each year. Deaths occur most often in infants under 6 months of age and among children in low-income countries.

In the US, RSV is among the leading causes of hospitalization for children under 5 years of age. A typical RSV season sends between 58,000 and 80,000 children under the age of 5 to the hospital and kills between 100 and 300, Center for Disease Control and Prevention estimates.

Researchers have been working to prevent and treat RSV for decades. But a dark cloud hung over the field for years, halting progress. It originated in the 1960s, when researchers began working on a vaccine against RSV. The experimental vaccine design used a standard treatment of the time – heat and a formaldehyde (formalin) solution to inactivate the virus and “repair” or stabilize its proteins. Thus, a formalin-inactivated viral vaccine could present a whole virion to the immune system that was incapable of infecting cells, but had all of its antigenic components essentially frozen in place so that immune cells could learn to target key components.

A disastrous candidate

But the vaccine was a tragic disaster. Not only did it fail to protect children from RSV in several clinical trials in 1966, it appeared to make children more susceptible to severe RSV.

For example, in a small american trial, researchers gave infants between 2 months and 7 months a three-dose regimen. Of the 40 unvaccinated infants in the control group, 21 were infected with RSV during a subsequent wave of infection in the community, and only one of the unvaccinated infants required hospitalization. Meanwhile, of the 30 infants who received the experimental vaccine, 20 contracted RSV, but 16 (80 percent) required hospitalization. Two of the children later died from bacterial pneumonia that developed after their RSV infection.

In the decades since, researchers have worked how it was the vaccine that caused the syndrome of “enhanced respiratory illness” (ERD) in vaccinated children. First, the formalin-inactivated RSV vaccine elicited weak antibodies that only weakly blocked and neutralized live virus. This impotent response led to accumulation of antibody-virus immune complexes which in turn activate worsening immune responses, including inflammation. The vaccine also boosted T cell responses that can trigger excessive inflammation in the lungs after subsequent RSV infection. All this can pave the way for serious diseases and complications, such as bacterial pneumonia.

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