058 - Immunity in Influenza: The Bearing of Recent Research Work

In 1939, people had already discovered the influenza virus, but there were still a lot of questions. For example, how can one distinguish between illness caused by this virus and very similar illnesses caused by many other things? And are all flu viruses the same? In this paper, C.H. Andrewes addressed these issues.

People had observed that major outbreaks tended to be the real flu, while minor outbreaks were typically something else. Andrewes called the former "epidemic influenza" and the latter "febrile catarrhs." Clinically, the real thing tended to be sudden in fever onset, and have more symptoms like headache and general achiness rather than the cough and sore throat characterizing other things. But there was a lot of overlap.

Mostly they tried to distinguish by infecting ferrets. The real flu tended to infect ferrets while the other stuff didn't. But it could've been possible to infect ferrets with more than one virus; it was hard to tell.

Serologically (that is, regarding the antibodies that bind to a virus), there seemed to be at least 4 different kinds of flu antigen. They hadn't found good ways to characterize these yet. Antibodies against one wouldn't bind as well, or at all, to another.

Regarding duration of immunity, they had found that in animals it lasted a few months, and Andrewes thought that duration seemed to correlate to body size, so it might last up to 1 year in people. Not sure if this is valid. But in any case, it declined over time, at least in ferrets.

In ferrets, subcutaneous vaccination worked for moderate immunity, not great. But moderate might be enough: humans wouldn't normally encounter very much flu at a time; and if it didn't prevent it completely, it could reduce the severity so that more people survived; and if people had some immunity already, it could increase it.

But studying immunity from vaccines is tough, because epidemics are infrequent and unpredictable. So people were trying to use antibody levels as a proxy. Some showed that antibodies and immunity correlated well, especially in ferrets, but it was unclear.

Andrewes tended to use a vaccine of virus inactivated by dilute formaldehyde. This seemed safer than a live attenuated vaccine, because a virus changed to be less virulent could always revert to become more virulent.

Lastly, he discussed the issue of when is best to vaccinate people. Epidemics in England were happening about every 4 years, but this wasn't reliable. Usually they happened in December or January, so the best time would be 1-2 months before, in October and November.

Citation: Andrewes, C. H. Immunity in Influenza: The Bearing of Recent Research Work. Proc R Soc Med 32, 145–152 (1939).