Down in the trenches of vaccine science with the dangerous meningococcus
The bacterium Neisseria Meningititis, also known as meningococcus, is a horrible pathogen. It can cause rapidly lethal infection. The infection comes in two forms. It can cause meningitis, inflammation of the surface of the brain, or it can just circulate in the bloodstream, a condition called meningococcemia. Some patients have evidence of both. You might think the brain infection is the worse of the two, but actually meningococcemia without meningitis has a far worse outcome. When the bacteria circulate in the bloodstream they cause profound shock, which can itself be fatal. They also activate the blood clotting system so the patient clots off blood vessels, leading to loss of limbs and worse. I’ve cared for more than a few patients with this infection, and it’s a dreadful one. The bacterium itself is actually quite commonly carried in the throat of well, normal people. It gets passed around by respiratory secretions. Invasion of the body is rare, and we don’t know why it happens in a few people and not everybody. We do know once the percentage of people in a confined area, such as an army camp or a college dormitory, who carry the organism reaches a certain point the risk of invasive infection rises quickly. There are many reports of epidemics in such settings.
Vaccines are designed to neutralize whatever pathogen they’re directed against. The immune system has several components that work in concert to accomplish this. Vaccines cause the body to produce antibodies, proteins that specifically bind to the surface of the microorganism. Antibodies call down other cells and blood proteins that recognize the red flag of the bound antibody and which destroy the bug. So the effectiveness of a vaccine depends on its ability to do this. Researchers typically measure blood levels of the relevant antibody as a proxy for effectiveness because it has been shown to neutralize the bug. You can verify that by what is known as a bactericidal test, in which blood components including antibody and other things are mixed with bacteria in a tube to see if it kills them.
Meningococcus comes in several related but distinct strains, as do most bacteria. We have an FDA-licensed, effective vaccine for all the strains except one, termed type B. These vaccines induce antibodies directed against the sugar coating (polysaccharide) on the bacteria. But type B has a surface polysaccharide similar to those on our own cells, and we don’t want antibodies against those things or they could also attack our own tissues. There is a vaccine, licensed in Europe, against type B meningococcus that chemists made by purifying six of the unique protein components on the bacterial wall and mixing them together in a vaccine. When injected into a person, that person makes antibody aimed at the components. But is that enough to kill the bacteria? That’s the bottom line. The answer turns out to be: more often than not, but not all the time. The safety of the vaccine has been shown, but its effectiveness leaves something to be desired. A recent paper and editorial in the New England Journal of Medicine is instructive. If you want to dive into the details of how vaccines are made and work it’s a good article to look at, especially the editorial.
There have been 7 outbreaks of type B disease during the past 6 years at US universities. The investigators studied the vaccine when it was used (with FDA approval) during a recent outbreak of type B meningococcal disease in New Jersey that caused 9 cases and 1 death. The vaccine was offered to 6,000 students, and this paper reports results from 607 of them. Of note, the strain causing this particular epidemic was shown to have 2 of the protein components contained in the vaccine. How well did it work?
Sixty-six percent of the students developed the ability to neutralize the strain of meningococcus that caused the outbreak. That’s not very good, really. When tested against the reference strain, the one used to make the vaccine, nearly 100% had neutralizing ability. Recall that the outbreak strain had at least 2 of the six protein components included in the vaccine strain. So one way to look at it is that yes, the vaccine induced immunity to the reference strain, but not so much to the strain that actually caused the outbreak. In the authors’ words:
Our results indicate that knowledge of [bacterial killing] immunity against the vaccine reference strains is not sufficient to predict individual-level immunity against an outbreak strain, even when the [outbreak] strain expresses one or more antigens that are closely related to the vaccine antigens.
So now what? I assume researchers just need to keep trying, although it’s a daunting task because there is quite a bit of variability among the proteins in type B organisms. Clearly hitting 2 out of 6 was not enough in this case. Should the vaccine be licensed in the US even though it’s not as effective as we would like? The editorialist puts things this way:
The regulatory approval and clinical use of vaccines for pathogens that cause outbreaks will remain challenging.
Yeah, I’d say so.