062 - Virus—antivirus mixtures in smallpox vaccination

Immunization against smallpox using vaccinia or cowpox virus was not always a harmless procedure (though of course better than getting smallpox itself!): it often produced an unsightly scar at the inoculation site, and sometimes at other sites; a general reaction could be problematic, especially in infants; and at worst, post-vaccinal encephalitis.

So people were trying to find a safer way of doing it. One way that seemed successful in animal studies was mixing the vaccinia virus with serum containing anti-vaccinia antibodies and inoculating that. Similar to how people vaccinated against diphtheria toxin using mixtures of toxin and antitoxin antibodies. Some found that such antibodies could prevent potent vaccinia from producing generalized lesions in rabbits, without reducing immunity too much, and others found that completely neutralized virus could still induce immunity when introduced nasally.

So Frisch wanted to find out if this could work in human children, and how. So he took two groups of children, 39 in one and 47 in the other, and immunized them using mixtures of virus and antibody-containing serum, in various proportions between 3:1 and 1:20 virus:serum. The first group got serum from children that had been vaccinated 5 years before, and the second from children vaccinated only 4 weeks before. After a while, he revaccinated some of them with pure virus to see if they seemed immune to it.

In the first inoculation, the virus mixed with 5-year serum seemed much more potent than that in 4-week serum, causing typical vaccinia reactions in almost everyone getting a mix of as low as 11% virus. That mixed with 4-week serum didn't consistently cause reactions unless the ratio was 3:1 virus to serum.

Did either of these induce immunity despite lack of reaction? The answer seemed to be no; most of the revaccinated children showed a typical vaccinia infection, unless they had received enough undilute virus to cause a reaction the first time. And waiting up to 9 months for immunity to develop didn't seem to change anything.

So antibodies against vaccinia seem to inhibit all its effects, both reactions and immunity. Too bad. Well, even if the children had shown immunity, I'm not sure how much it would mean, since it'd be immunity to vaccinia rather than to smallpox, though there would probably be at least some overlap.

The other interesting thing is that it showed that levels of antibodies from vaccination did decrease over 5 years, so that the serum was less potent in neutralizing the virus. Did this mean the 5-year serum donors were no longer immune? Can't tell from this study: it might not take very much to protect against infection. It just shows their levels were relatively lower than the others, not necessarily inadequate.

Citation: Frisch, I. A. Virus—antivirus mixtures in smallpox vaccination. Am J Dis Child 49, 894–899 (1935).