November 7, 2019

9: Measles in Highly Vaccinated Populations

Did the measles vaccine perform as it was intended? Even in highly vaccinated populations, outbreaks still occur. Why?

9: Measles in Highly Vaccinated Populations


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Now, the measles vaccine has been introduced, it's been in widespread use. What I want to look at now is what happened to measles in highly vaccinated populations, those populations where there was a very high uptake according to the CDC recommendations and I want to look specifically at the period 1981-1991. How did the real world experience with measles vaccination for example, reflect the validity of the original reassurances of lifelong immunity from a single shot, that were given at the National Institutes of Health in 1961. At that meeting, caution had been expressed by Sir Graham Wilson and Dr. Enders himself who isolated the original measles virus about the use of a vaccine that might not produce immunity that was as robust, as that following natural infection, and that vaccination should not leave people more vulnerable to measles at an age of infection where it may be more dangerous, very early in life, or as adults.

Now, after the decline in measles shown in this graph reflecting the United States in black and Mexico in green, we see a fall in the morbidity, the number of cases of reported measles. Again, what's interesting... Just to note that in Mexico, you see a fall in the reported number of cases steadily before the vaccine was introduced, this doesn't mean that measles was not circulating or infecting people but as I've said before, what I think this reflects is a lower number of reported cases because there was an increased number of very mild cases that were not typical of measles and therefore were not reported as such.

Nonetheless, what we find in the time around 1990 was a resurgence of measles both in Mexico and the US. I want to look at that period in particular. The early observations after the introduction of measles in the '70s and '80s, that measles outbreaks in school-age children accounted for the majority of reported cases, in other words, measles during the standard time at which children historically contracted this disease and according to the sources cited by Wood and Brunell 42% of affected children, those who had measles had already been appropriately vaccinated against the disease. In other words, there was already emerging a failure rate of the vaccine itself. In 1989, there were then 170 outbreaks in school-age children. This is up from around 40 to 50 on an annual basis. This increased through 1990, now with the majority affected either school-age or college-age, so there is an apparent displacement of the age of measles upwards into college age students and this is unusual. Once again, approximately 80% of the school-age children affected by measles had been appropriately vaccinated. In another example, an outbreak was sustained in two Texan schools despite a nearly 96% of the students having immunity, that being an antibody-positive to protection against measles virus.

The conclusion from that is that epidemics of measles can be sustained in school-age populations despite very high vaccination rates, and this was beginning to run contrary to the idea that measles was going to be rapidly eradicated from the population using the single measles vaccine. It appeared that one dose did not protect in the way that natural measles protected, that is life-long. Later, in the '89-'91 epidemic, there was a dramatic shift from older children now to pre-school children to younger children, 81% of net who were now un-immunized and in 1990, this was highest for children under one year of age in that critical period when they were more susceptible to severe outcomes from the disease. Among affected children in the 15 months to four-year group, again 44% were fully immunized, death rates, not un-surprisingly, were highest among the younger children. And you can see here in this table, at the top, age group under one as we get later and later into the epidemic period, up to 1990, then we see a dramatic increase in the incidence of measles cases specifically in those under one. So the initial assumptions and assurances were wrong.

For some reason, an imperfect vaccine had violated Wilson's concerns that measles vaccination should not shift the age of susceptibility to one where the disease was more dangerous, the shift in age, and therefore the change in morbidity and mortality that was seen for example, in children under one was in some way a consequence of the vaccination strategy. Why? The feeling at the time that this was non-compliance, it was people not having the vaccine, but the fact that 42-80% of those affected had actually been vaccinated on schedule meant that that could not be the only explanation. There was primary vaccine failure. That is that not all children developed immunity following exposure to the vaccine. A proportion for whatever reason, were not becoming immune. Secondary vaccine failure, that the immunity that the vaccine did produce was not sustained, unlike natural infection where it is sustained for life, this vaccine-induced immunity was... Appeared to be falling off quite quickly and represented secondary vaccine failure. There is something else that is rarely talked about, but that is tertiary vaccine failure and that is declining vaccine efficacy over time by virtue of the way in which the vaccine is made, it may be getting weaker and weaker and weaker.

Finland was extremely instructive. There was an outbreak in 1989, and what was described as an explosive school outbreak in a rural Finish municipality. 51 measles patients infected in one school at home or elsewhere were compared by Dr Peltola and his colleagues with 214 healthy controls to see what factors operated to determine who was at risk. Those infected later at home, secondary cases. If you remember our description of those infected in school or in the community compared with those infected at home, those getting infected at home were at higher risk of intensive or high dose exposure. These children had a higher measles risk, even if they'd received two doses of MMR, so intensive exposure appeared to overcome the immunity that was created by even two doses of the vaccine.

When siblings shared a bedroom, even higher intensity exposure with a measles case, then there was a 78% risk observed of measles occurring among vaccinees. So the more intensive the exposure that you had with natural measles, the greater the risk you had of overcoming vaccine-induced immunity and developing measles disease. Vaccinees had a shorter incubation time than un-vaccinated and that was an interesting observation. The natural presentation of measles appeared to have changed. Vaccinated and un-vaccinated students were equally able to infect their siblings.

And in conclusion, total protection against measles might not be achievable even amongst re-vaccinees, those who've had two doses when children are confronted with an intensive exposure to measles virus. Clearly the measles vaccine failure was far more complex than had been assumed. In Canada, there was a similar outbreak. In 2011, there was an outbreak in which over 50% of the 98 individuals who had measles had received two doses of measles vaccine. Nine percent of children having two doses of vaccine will have lost their immunity after just seven years and as more time passes, more children lose their immunity. The secondary vaccine failure. As Greg Poland has noted, this leads to a paradoxical situation whereby measles in highly immunized societies is now occurring primarily among those previously immunized. So, why so much measles in vaccinated children? Well, we have the first point is that the vaccine doesn't induce immunity in everybody. There is a certain percentage, perhaps 5-10% who will not develop adequate immunity against measles, in the face of the vaccination. Then, over time, the immunity induced by the vaccine wains, it falls off. Secondary vaccine failure unlike natural infection vaccine-associated immunity does not last life long.

The other thing is that we measure immunity by antibody testing and so it's reasonable to ask is antibody testing an adequate measure of immunity and these authors in the same paper make the comment that serological antibody testing for measles has been problematic and has been fraught with false positive and false negative results. So are we to believe the studies based upon laboratory tests that have relied upon antibody testing to tell us whether children are or not protected for measles. And as I said, declining vaccine efficacy over time or tertiary vaccine failure is a real problem without going to great detail on how this is done. Mutation of the virus over time is a problem inherent in the way live viral vaccines are made.

Once the virus, the attenuated or weakened virus is obtained, it's propagated in tissue culture. The original parent vaccine virus is not used to produce subsequent vaccine lots. It's the progeny of the original parent that is used to become the new parent and so on, and so on, and so on. And sufficient to say that it's a problem inherent in how these vaccines are made, that vaccine potency changes over time, likely as a consequence of accumulated mutations and we've seen this again with the mumps vaccine of Merck. Let's look at this now, in the context of the original assurances given to doctors and the public pursuant of 1961. There would be protection from a single shot of the attenuated vaccines. Measles immunity would be lifelong, and measles would be quickly eradicated. Age distribution of cases later in the epidemic period.

Age distribution of cases later in the epidemic period with the greatest percentage increase in pre-school children is, therefore, most alarming. We saw exactly what was countenanced against, what was warned against by Wilson and his colleagues, is that vaccination-policy had shifted the age of susceptibility to a time when morbidity and mortality was greater, 35% of cases and 60% of deaths were seen in the pre-school children. And deaths were not necessarily a function of measles per say, that, of age of measles infection which in turn was a function of the vaccination strategy. So in conclusion, the National Vaccine Advisory Committee concluded the primary cause of the 1989-91 epidemic was due to widespread transmission among un-immunized preschool and minority children. The problem is clearly far more complex than that.

There is widespread transmission among the vaccinated, antibody testing for immunity is misleading at least, and the age distribution of the cases developing measles in the face of widespread vaccination is very alarming. The response of the authorities and the industry has been to increase the number of doses. It started with the second dose at five years, and now there is a dose at college entry. And as we go on, and on, and on, through this process of waning vaccine efficacy how many doses are we going to end up needing? We are going to be a society reliant upon multiple doses of a vaccine that is not working, but has pushed our age of susceptibility to a point where if we then get measles, do we become vulnerable to a severe infection? And so, the exercise here is please become familiar with the terms primary, secondary, and tertiary vaccine failure and try and predict what problems might arise as a consequence of these unexpected and unintended limitations of live viral vaccine.