034 - A Yellow Fever Vaccine

Back in 1928, yellow fever was causing problems in West Africa, causing epidemics and killing people who went there to investigate it. It’s caused by a virus that’s in the Flavivirus family, related to dengue and West Nile, and all these are transmitted by mosquitoes. The symptoms of yellow fever are usually fever, chills, nausea, muscle pain, and headache (among a few others), but sometimes it can go toxic and cause fatal liver damage. It’s classified as a hemorrhagic fever because it increases bleeding . Usually the mortality rate is 3% of cases, but can get as high as 50% in some outbreaks.

So, at a time in medical history when people were just learning that some infectious agents are smaller than bacteria, Edward Hindle isolated the yellow fever virus and attempted to make a vaccine against it.¹

He got the virus from a case of yellow fever in Dakar, Senegal. It was maintained by passing it through rhesus monkeys via mosquitoes; not a simple routine procedure, sounds like, not exactly streaking a Petri dish. But it worked: when he inoculated 16 other monkeys with only 1 μg of infected monkey liver, they uniformly died after a few days. It seems a lot more severe in these monkeys than in humans, but it makes for a good animal for vaccine tests I suppose.

So Hindle tried two different but similar ways to make a vaccine: the first used formaldehyde in saline to inactivate the virus, and the second used phenol in glycerin and water. In each case, some liver and spleen from an infected monkey was mixed with these ingredients, then filtered through a cloth and inoculated into test animals.

Hindle tested the formaldehyde version in one subject. It had a slight, short fever after immunization, but when inoculated with a dose of yellow fever that was about 2000 times more than a dose that would be lethal in most cases, the monkey only had a mild fever for 4 days. Two controls that received 1- or 10-times lethal doses both died as usual. Even a 10000-times lethal dose in the vaccinated monkey didn’t make it very sick.

So that’s pretty good, but the other was even better. The first monkey to get it had barely any reaction, if any, but resisted a 2000-times lethal dose with no symptoms, and then another 10000-20000-times dose.

Hindle was so pleased with these results that he tested another 10 monkeys (6 vaccinated, 4 controls). These 6 didn’t show any adverse reactions either. A second, blinded researcher inoculated the 10 with about a 10000-times lethal dose. All controls died as usual, but only one vaccinated died (who had actually received about 20000-times lethal dose); the other five were fine.

These seem like promising results, essentially a “yes or no” answer of whether the vaccine worked. There were controls involved and some blinding, though no placebo (not so important when doing an animal study though, perhaps). The author said human trials were worthwhile, though some tests should be done to determine the duration of immunity and the vaccine’s shelf-life.

However, future articles citing this study didn’t take such a bright view of it:

"Both preparations appeared to protect monkeys against yellow fever, but subsequent investigations of efficacy were inconclusive."²

"Overall, these preparations were problematic due to residual live virus or were ineffective due to inadequate antigenic potency, reflecting the rudimentary virological methods available at the time."³

"Results with this vaccine in human subjects were considered promising, though immunogenicity was described as irregular. Further attempts at refining and optimizing an inactivated YFV (yellow fever virus) vaccine however, were abandoned following the development of cost-effetive live attenuated yellow fever strains that were highly effective at protecting against natural YFV infection. These early attempts at developing an inactivated YFV vaccine were left behind as failures and this perception has persisted despite signs of early success."⁴

"The problems described with these vaccines were the presence of residual infectivity in viral preparations or the loss of immunogenicity."⁵

So I guess there are better YFV vaccines coming up in future posts.

Citations:

1. Hindle, E. A Yellow Fever Vaccine. Br. Med. J. 1, 976–977 (1928).

2. Hayes, E. B. Is it time for a new yellow fever vaccine? Vaccine 28, 8073–8076 (2010).

3. Monath, T. P. et al. Inactivated yellow fever 17D vaccine: Development and nonclinical safety, immunogenicity and protective activity. Vaccine 28, 3827–3840 (2010).

4. Amanna, I. J. & Slifka, M. K. Wanted, dead or alive: New viral vaccines. Antiviral Res. 84, 119–130 (2009).

5. Gaspar, L. P. et al. Pressure-inactivated yellow fever 17DD virus: Implications for vaccine development. J. Virol. Methods 150, 57–62 (2008).