Why the success of Pfizer’s RSV vaccine is a big deal has been decades in the making
As an unusually large and early seasonal surge in RSV cases overwhelms 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.
The company’s experimental RSV vaccine—given to pregnant trial participants—was 82 percent effective in preventing severe RSV-related lower respiratory tract illness in the first three months of an infant’s life. It was 69 percent effective during the first six months, Pfizer said.
“We are thrilled with these data because this is the first investigational vaccine that has been shown to help protect newborns from severe respiratory disease associated with RSV immediately after birth,” Pfizer Chief Scientific Officer Annaliese Anderson said in a statement.
The company said it plans to file for regulatory approval with 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 announced only top results in the press release. The data will have to undergo a more detailed external verification. 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 non-severe RSV-related lower respiratory tract disease—although the company says some efficacy was clinically significant.
Still, there’s reason to be excited about Tuesday’s news, which follows decades of researchers battling RSV. This includes the disastrous vaccine trial in the 1960s, which caused 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 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 number 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 more than 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, assessment by the Centers for Disease Control and Prevention.
Researchers have been working on the prevention and treatment of 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 design of the experimental vaccine used a standard treatment of the time – heat and a formaldehyde (formalin) solution to deactivate the virus and “fix” or stabilize its proteins. Thus, a formalin-inactivated virus vaccine could present a whole virion to the immune system that was incapable of infecting cells, but with 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, but it also appeared to make children more vulnerable to severe RSV.
For example, in a small American trial, researchers administered a three-dose regimen to infants between 2 and 7 months of age. Of the 40 unvaccinated infants in the control group, 21 contracted RSV during a subsequent wave of community infection, 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 on it 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 immune complexes antibody-virus which in turn activate worsening immune responses, including inflammation. The vaccine also stimulated T cell responses that can cause excessive inflammation in the lungs after subsequent RSV infection. All this can pave the way for serious diseases and complications, such as bacterial pneumonia.