The flu comes back year after year, and every season we get vaccinated (well, some of us anyway). Why do we need to keep getting a new shot for the flu while for others, like measles, we got way back in childhood and are done with it for the rest of our lives?
Our immune response to influenza involves production of antibodies, large proteins that specifically bind to the virus and help clear it out or neutralize it. It seems like the key to influenza immunity is neutralizing antibodies, antibodies that bind to the virion and prevent it from attaching to the host cell. You can imagine this large protein just being physically in the way, preventing the virus from binding the host receptor. The immune response that develops from natural exposure or vaccination generates neutralizing antibodies to HA, a viral envelope protein that is necessary for attachment to the host. I’ve mentioned HA in a previous post about influenza. The problem is that last season’s neutralizing antibodies dont bind to this season’s virus. Although it may be nearly identical to the virus from a past season, the new strain’s HA is slightly different, and those differences are enough to evade existing neutralizing antibodies.
Now a new approach to vaccination has shown that it may be possible to develop a vaccine that illicits broadly neutralizing antibodies, that is, antibodies that will protect against influenza strains with slightly different HAs. They used a prime/boost approach, in which a DNA vaccine was used to induce an initial response against HA, and then boosted with a regular seasonal flu vaccine. The only difference between this and what is currently done is the addition of the DNA vaccine. However the response seems quite different. Neutralizing antibodies were generated that can neutralize a variety of different influenza viruses. It seems the vaccine induced antibodies to a different part of HA. Antibodies are so specific, the dont recognize the whole HA, but rather discrete parts of it. The part recognized by these antibodies, called the stem, is highly conserved, meaning it doesnt change season to season.
This raises many interesting questions and possibilities. Could we soon have a universal vaccine that will protect us for life or at least for many years? Why did the change in vaccine regimen induce antibodies to a different part of HA? Why does the current vaccine or natural exposure fail to develop antibidies to the conserved portion of HA? Will the conserved portion of HA eventually change too, if sufficient selective pressure is applied through mass vaccination?
The 1918 influenza pandemic (the “Spanish Flu”), by some estimates, killed as many as 100 million people in a very short period of time. The 2009 “Swine Flu” pandemic didnt kill so many, but it spread rapidly and widely across the globe. Despite that difference, it turns out the two viruses responsible for these pandemics have some important similarities.
Influenza virus has a protein on the surface called hemagglutinin, or HA, which is used to attach to host cells, allowing the virus to then enter and replicate. HAs change rapidly, which is partly why influenza keeps coming back. When HA changes, your antibodies dont recognize it so well, so you get sick again. It turns out that the HAs of 2009 and 1918 are similar on both the sequence and structure level. There is a small patch on the HA protein that is 95% identical between 1918 and 2009 but only 70% identical to seasonal strains. Looking only at the 3D structure, among all influenza HAs, the 2009 HA is most similar to the 1918 HA. The 1918 and 2009 HAs also lack glycosylation at the tip, while seasonal influenza viruses HAs are sugary.
Why is that interesting? An unusual pattern was noted in the 2009 pandemic: elderly people were not as affected as younger people, the reverse of what is usually seen with influenza. It was proposed that perhaps some people still had immunity to the 1918 virus, which continued to circulate for many years after 1918, and that immunity was cross-protective. A recent study shows that this indeed seems to be the case. Mice immunized with the 1918 virus are protected against the 2009 virus. The converse is also true: if you immunize mice with the 2009 virus, they are protected against the 1918 virus. That’s pretty impressive when you consider that one season’s vaccine might not protect you from next season’s virus. It seems the immune system cant really tell the difference between these viruses. Note that it also tells us how long immunity can last! The next question is, how and why has this HA structure come back?
There are only a few places in the world where polio is still endemic. Polio normally infects the gut and is usually asymptomatic, but sometimes spreads to the nervous system and causes acute flaccid paralysis (AFP). In South Asia, AFP keeps cropping up, but it turns out many of these cases are not being caused by poliovirus. So what is causing these cases of AFP? A recent study did a metagenomic analysis of the virus population from stool samples from AFP cases in Pakistan. Metagenomics is an approach where you can sequence all the nucleic acid from a particular sample to see whats there. In this case they filtered samples to remove cells, digested the filtrate with nucleases to destroy free nucleic acids, leaving them with the genetic material of viruses in their protective capsids.
They found lots of bacteriophages (presumably infecting gut bacteria), lots of plant viruses (probably from eating veggies), and lots of animal viruses. They identified a new genus of picornaviruses, closely related to poliovirus. This new genus, which they called Cosavirus, appears to be highly prevalent in samples from Pakistan but not in samples from the UK. But is it the cause of AFP? Its found in 49% of AFP cases and in 44% of healthy controls. So are healthy controls asymptomatic infections, like we see in polio? Are there other causes for the other 51% of AFP cases? Lots of questions obviously remain in understanding the epidemiology of AFP here, but this study is a good start and a very practical application of metagenomics for virus discovery.
CCHF is disease that is usually transmitted by contact with blood of infected animals, usually farm animals, or ticks. As such, most people infected work in agriculture or butchering and tanning. In rare cases, CCHF transmission has been observed to occur in hospital settings, such as through the use of contaminated instruments or contact with infectious blood. There appears to be an outbreak in Pakistan and Afghanistan, although at the moment its not clear how the cases are related, if at all. 7 cases were reported in Helmand Province, Afghanistan in June 2010. Several others have been reported in Pakistan since March and there are several cases of “undiagnosed illnesses” in the area which may be CCHF. Initial cases were reported in the expected populations: a butcher, a tanner and other agriculture workers. However the disease appears to be spreading rapidly in hospitals too. 8 individuals at a hospital in Islamabad tested positive for the virus. A doctor in Abbottabad who died of the disease may have spread it to his brother.
It seems like many of these cases are the result of human-to-human transmission rather than tick bites or from contact with animals. The reason for prevalence of this unusual transmission pattern in this particular outbreak is not known yet.
In 1980, smallpox was declared eradicated following an intensive global vaccination campaign. The virus, Variola, has some close relatives that can infect humans, one of which is monkeypox. Monkeypox isnt nearly the problem that smallpox was; it has a much lower mortality rate and outbreaks tend to fizzle out quickly due to poor human-to-human transmission.
However, a recent paper suggests that monkeypox infections are becoming an increasing problem. So why is it emerging now? Its a problem we’ve been anticipating, actually. Turns out that when you get the smallpox vaccine (or smallpox itself), it also protects you from monkeypox. So pre-eradication, most people were immune to monkeypox. If you met up with an infected animal, chances are you were immune and wouldn’t get infected. If you did somehow get infected, chances are most people around you were immune so you couldn’t transmit it to others. An immune host is not fertile ground for viral replication, so whenever immune hosts are encountered, the chain of viral transmission ends. In fact, a highly vaccinated population helps those few individuals that are not vaccinated by greatly limiting the potential of the virus reaching the unvaccinated (“naive”) individual. Thats called herd immunity.
Turns out herd immunity to smallpox, and therefore monkeypox, is waning. Vaccinations stopped in 1980 so anyone born after that is naive and therefore there is a major lapse in herd immunity. Risk of infection with monkeypox virus is now as much as 20 times greater than 30 years ago. Interestingly, all those old people born before 1980 who were vaccinated have a much lower risk of infection, telling us that immunity from vaccination lasts 30+ years.
So why should we worry about waning herd immunity to a rare and relatively mild disease that is hardly contagious? Well, variola and monkeypoxviruses are about 96% identical. We dont know how much monkeypox needs to mutate to become sustainable in humans or more virulent.