Immunologists show how deaths in 1966 could have been avoided.
A catastrophic vaccine failure that killed two toddlers could have been averted if adjuvants — chemicals that prime the immune system — had been added to the vaccine.
In 1966, a vaccine was tested in the United States against respiratory syncytial virus (RSV) — which infects almost all children before they turn two1. The tests had dire consequences: Children weren't protected; many infants still caught RSV, suffered worse symptoms than usual, and needed to be hospitalized; and two toddlers died as a result of enhanced disease symptoms2. And a safe vaccine for the disease has still not been found.
Studies have since shown that formalin — a chemical that is used to kill viruses when making vaccines — deformed the virus, suggesting that the failure was largely a result of the vaccine triggering the creation of poorly designed antibodies3. But Fernando Polack, of Johns Hopkins University in Baltimore, Maryland, wasn't convinced. "It had to be more than the formalin," he says.
Polack suspected that affinity maturation — the process by which antibodies become highly tuned to hunt down specific pathogens — might have been involved.
To test the idea, Polack and his team looked at RSV infection in two groups of mice. One set had their lymph nodes removed, crippling their immune system so that affinity maturation couldn't take place. They were inoculated with the live virus, which hadn't been deformed using formalin.
In another set, they examined what happened when mice were protected with a formalin-inactivated vaccine, similar to the vaccine used in 1966, that had been tweaked with Toll-like receptor (TLR) agonists — adjuvants that boost affinity maturation.
When affinity maturation was blocked, mice didn't develop protective antibodies against infection. By contrast, when affinity maturation was chemically boosted, mice didn't suffer the enhanced disease symptoms that marked the 1966 failure.
Polack and his colleagues conclude in Nature Medicine that the 1966 vaccine didn't generate protective antibodies because the immune system hadn't been adequately primed2. Moreover, had TLR agonists been added to the vaccine, the failure might have been averted. Sadly, there was no knowledge of TLRs in 1966, says Polack.
"Polack's findings fit in with a trend in the vaccine industry on using really good adjuvants," says Peter Openshaw, director of the Centre for Respiratory Infection at Imperial College London. "They show that you can make better vaccines by being selective about which types of pathways you activate."
The findings, however, will not immediately end the 40-year hunt for an effective vaccine against the disease.
Ultan Power, who works on RSV at Queen's University Belfast, cautions that "great care must be taken in the choice of TLR agonist", as the wrong choice of agonist can also lead to vaccine failure. "Because of what happened in the 1960s, there is a huge concern for anybody to take the first risk," adds Power.
While various groups continue to work on developing vaccines to prevent RSV, doctors do have one very expensive recourse — Synagis (palivizumab), an antibody therapy that is produced by the biotech company MedImmune.
Unfortunately, a course of Synagis costs around US$5,000, says Openshaw, so it is only administered to high-risk, such as premature, babies where medical insurance covers the costs, such as in the United States. "MedImmune has made huge amounts of money on Synagis," says Openshaw.
"There are some vaccines that came very easily, but developing a vaccine for RSV is very tricky," says Polack. But, he adds, a vaccine for the disease is urgently needed.
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Delgado, M. F. et al. Nature Med. doi:10.1038/nm.1894 (2008).
Moghaddam, A. et al. Nature Med. 12, 905-907 (2006).