RSV: Hunt for a Vaccine, Inactivated?

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When I admit an infant to the hospital with RSV bronchiolitis I get the same questions from the worried parents that I got 39 years ago when I was an intern: “Can you give my baby something to help him breathe better? Can you give my baby an antibiotic or anything to help him get over this faster?” Sadly, for the most part, the answers have not changed in 39 years. I inform the parents that we will give the child the extra oxygen he needs, IV fluids if he gets dehydrated, but that we don't have anything other than supportive care to offer.

Has anything changed in nearly 4 decades of vaccine research? Let’s see what you recall about the fight against RSV.

1. How many babies with RSV younger than age 1 year require hospitalization annually?

A. About 1 in one thousand

B. About 1 in one hundred

C. About 3 in one hundred

D. About 5 in one hundred

Click here for answer, discussion, and next question.

Answer: C. About 3 in one hundred

Hospitalization rates are highest in the first 6 months of life and certain populations (preemies, babies with chronic lung disease, etc.) are at higher risk, but overall about 3% of children under the age of one year are hospitalized; most hospitalizations occur in healthy-term babies. Synergis, a monoclonal antibody against RSV, is given to those at the very highest risk, but its high price prevents universal use.  

Given the high number of hospitalizations per year, more than 100,000, a safe, effective RSV vaccine is an attractive target for biotech companies. In 1966, a formalin inactivated vaccine was given to children in clinical trials but was eventually not approved.

2. What was the reason?

A. It worked well in animal models, but efficacy was poor in humans.

B. Efficacy was fair in the human trial, but side effect profile was poor (high fever, limb swelling, and excessive crying).

C. It interfered with the immune response to the DPT shot given at the same time.

D. Not only was it ineffective, but children who received the vaccine had more severe disease than the children receiving the placebo.

Click here for answer and discussion.

Answer: D. Not only was it ineffective, but children getting the vaccine had more severe disease than the children receiving the placebo.

Children receiving the vaccine developed more severe disease on average than the children who got the placebo. Two children receiving the vaccine actually died. Perhaps the formalin distorted some of the viral antigens which lead to creation of antibodies that overstimulated the immune system while not attacking the RSV virus. No one knows for sure. Needless to say, further attempts at producing an inactivated vaccine were put on hold.

Forty years later, several live, attenuated vaccines are in trials, with one to start phase 3 testing, the final stage in clinical trials before seeking FDA approval. Several factors make RSV vaccination in infants a tough proposition: first, infection with RSV does not confer complete immunity. Most people contract RSV multiple times throughout their lives. In fact, the elderly are a high-risk population and any new vaccines will be tested in that age cohort. A human's first infection, however, is the one most likely to result in hospitalization.

Second, infants younger than age 6 months are at highest risk, but given the poor protection from a single natural infection it is anticipated that multiple doses will be needed. Think of the pertussis vaccines: good immunity does not happen until after the 3^rd dose at 6 months of age. Thus, an effective RSV vaccine might be a good option for adults and might help infants through the development of herd immunity, but will be unlikely to reduce the burden of disease in the group at highest risk, the child under 6 months of age unless...

A way out of this clinical conundrum may exist. Click here for RSV Vaccine: Just for Kids? in which I talk about how an RSV vaccine, either a live or inactivated one, may still be of great benefit to our infants.

Resources

 A study showing the increase in RSV hospitalization rates from1989 to 1996:

 â–º Shay DK, Holman RC, Newman RD, et al. Bronchiolitis-associated hospitalizations among US children, 1980-1996. JAMA. 1999;282:1440-1446. doi:10.1001/jama.282.15.1440.

A look back at the failure of the first RSV vaccine with some theories as to why it didn't work:

 â–º Mullard A. Vaccine failure explained [News]. Nature. Published online 12 December 2008.