Today, I read an unusual clinical trial that tests a theory called "heterologous immunity". This theory postulates that humans have a type of general immunity that is not specific to the antigen. Therefore, administering existing non-Covid19-specific vaccines may give a kind of halo effect that offers protection against Covid-19. The benefits of such an approach is that we'll be able to use proven vaccines that have better safety profiles, are widely available, are cheaper for less developed nations, and have more solid years or decades of research behind them.
The study was conducted at the Federal University of Santa Catarina in Brazil. About 400 health workers at the University Hospital enrolled in the double-blind, placebo-controlled clinical trial. The vaccine arm got two shots of the MMR vaccine 8 weeks apart; the placebo group received two shots of saline solution on the same schedule.
The result is fascinating: the MMR vaccine had efficacy of 10%, that is to say, the infection rate of the vaccine arm was 90% that of the placebo arm. The VE of 10% is not statistically different from 0%.
If you've been reading this blog, you'd know that such a VE number means nothing unless you know exactly how they count cases. I'm happy to report that the above number is completely devoid of any kind of tricks. They are counting all infections, based on positive PCR test results, regardless of symptoms. They are counting every case from first shot, thus no case counting window. There is no secretive adjudication committee to inject subjective criteria into case counting.
What is fascinating is that about half of the cases in the vaccine arm were asymptomatic, compared to 20% in the placebo arm. In other words, the MMR vaccine does not prevent infection but among those infected, the health workers were more than twice as likely to experience no symptoms. You have heard this story before - that sounds like what they are saying about the mRNA vaccines.
So, the MMR vaccine - if deployed against Covid-19 - would be a prototypical "leaky" vaccine. The mRNA vaccine also appears to be leaky but not to this extent. Whether this is a bad thing depends on whether asymptomatic people have high enough viral loads to transmit the disease. What's certain is that - if they are infectious - they are even more likely to be spreading the disease since they won't know they are infected. The study did not measure viral loads, so this question is left unanswered.
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The researchers now compute the outcome measures we have come to expect from these vaccine trials. They reported a 50% VE for symptomatic, PCR-positive Covid-19, and a 78% VE for "Covid-19 requiring treatment".
These alternative VE measures each involve discounting some of the cases in the earlier number, typically resulting in higher VE values. To get from the 10% VE to 50% VE for symptomatic Covid-19, about 50% of the cases are removed from the vaccine arm, and 20% from the placebo arm. Then, going to 50% VE to 78% VE involves removing mild cases.
It's frustrating that the research community refuses to standardize key definitions. The so-called Covid-19 requiring treatment sounds like hospitalizations but it's more than that to this Brazilian team. To count as requiring treatment, the participant must have a positive PCR test, respiratory or clinical symptoms, and treatment such as "anti-coagulation, corticosteroid and antibiotic therapy or hospitalization".
Statistics has become collateral damage during this pandemic. I find yet another proof in this study. These researchers overlook the huge margins of error associated with the above estimates: the margin of error on the symptomatic VE is 31% to 78%, and that on the "requiring treatment" VE is - gasp - from 6% to 82%. When ignoring these, they are acting just like the average vaccine researcher.
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These researchers - to their credit - did not apply a 2D+14 day case counting window. Doing so removes even more cases from the count, resulting in an even higher VE. If they have added the case-counting window, plus subjective adjudication, it's likely that the MMR vaccine would become competitive with the lower end of Covid19-specific vaccines.
That can be interpreted as evidence of "heterologous immunity" or "grade inflation". By grade inflation, I mean, the metric may have be defined in such a way that it sets a low bar.... just like in many colleges in the U.S., it's much harder to not get an A than to get an A.
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Let's contemplate that a bit more. In the Brazilian trial, the average rate of infection was 25% (remember this is about the same across both arms). The median follow-up time was 5 months (unclear whether this is counted from first dose or second). Roughly speaking, the Pfizer study reported cumulative case rate in the placebo arm of 6-7% about 5 months counting from 1st dose. Why such a huge gap?
I have already mentioned two factors contributing to the wide divergence in case rates. The Brazilian number counts asymptomatic cases while the Pfizer number excluded cases by adjudication.
The authors believe that the high infection rate is due to high exposure at the hospital. If true, it provides a little information on something we have so far been blinded to: how many of the uninfected participants in any trial have been exposed to the virus, and how many simply have not gotten exposed during the study period?
The higher exposure factor is balanced by the favorable demographics: the Brazilian participants are generally young (less than 10% over 50 years old), and healthy (most have no co-morbidities).
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On the topic of comorbidities, the table excerpted below includes some intriguing data: (remember the allocation is 1.5 vaccine to 1 placebo)
The two co-morbidities that exhibit the highest infection rates (almost 80%) - hypertension and diabetes - are skewed towards the placebo participants while the MMR vaccine arm has more smokers, who surprisingly show a 12% infection rate, half that of the average in the trial. None of these observations are statistically significant because of small sample size. What the table shows is that in small samples, randomization does not guarantee balance on all variables.
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The result from this study makes me wonder whether such vaccines can be used as booster shots.
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