20 August 2021 Blog Post: Evidence(?) for Boosters

20 August 2021 Blog Post: Evidence(?) for Boosters

Last Friday’s announcement by the CDC that certain groups who may not have mounted an adequate immune response to the current 2 series COVID-19 vaccine, was quickly followed this Monday by rumblings that the Biden Administration was poised to make a general recommendation for a 3rd “booster” dose. This was confirmed Tuesday during a press briefing with the who’s who of federal scientists.  Boosters would be set to occur 8 months after one’s second dose for the Pfizer and Moderna mRNA vaccines. Guidance for the J&J/Janssen single dose vaccine would follow but is also widely anticipated to have a booster recommendation.

The World Health Organization (WHO) vehemently disagreed with the US booster decision. The organization’s top scientist, Dr. Soumya Swaminathan, said the evidence does not show boosters are needed for everyone, and she warned that leaving billions of people in the developing world unvaccinated could foster the emergence of new variants and result in “even more dire situations.” Or, more succinctly said,  “We’re planning to hand out extra life jackets to people who already have life jackets, while we’re leaving other people to drown without a single life jacket,” said Dr. Michael Ryan, the WHO’s emergencies chief.

So what is the evidence for boosters?

The first paper worth reading (links at the end of this post) is from Mayo Clinic and nference (yes I spelled that correctly – a data analytics company); 10 of the 12 named authors all report a financial stake that would benefit them directly from a “successful” research outcome (i.e. recommending boosters). The study design is pretty ingenious – they use ‘matched triples’ wherein they compare demographically and clinically similar triads which include an unvaccinated individual, one who received Pfizer vaccine and a third who received Moderna.  There were 25,869 sets of matched triples (so a total cohort of 77,607)  The research team then tracked the number of breakthrough infections (positive test result), hospitalizations, ICU admissions and death providing a monthly estimate of vaccine efficacy. 

But before we grind down into month by month data, let’s look at the Minnesota picture only (these data are buried in Tables 2 and 7 of the paper). The authors split out events occurring 14 days after the second dose, which is a reasonable way to tally breakthrough events, as full vaccine effectiveness would be expected two weeks after the second dose. Because of dropouts or patients lost to follow-up, there are fewer that the 25,869 in each group

For Moderna:  There were 38 breakthrough infections (n=21179), 6 hospitalizations (n=21187), 1 ICU admission (n=21187) and 0 deaths (n=21187).

For Pfizer:  There were 72 breakthrough infections (n=22064), 11 hospitalizations (n=22085), 2 ICU admissions (n=22090) and 0 deaths (n=22092).

Among Unvaccinated:  There were 321 breakthrough infections (n=24990), 82 hospitalizations (n=25083), 17 ICU admissions (n=25097) and 4 deaths (25101).

These data make a pretty compelling case for vaccination.  Among those who are unvaccinated the risk of a positive COVID test is five fold, hospitalization 8 fold, ICU admission nearly 10 fold.  One’s mortality risk cannot be calculated as nobody vaccinated for COVID-19 died. Moderna does appear to be ‘better’ at protecting against infection, hospitalization and ICU admission – but mortality is zero in both vaccinated groups.

But what about a booster shot?  The rationale given by the authors is that vaccine immunity wanes over time and that a third jab is needed to provide additional protection.  This is nicely detailed in Table 3 of the paper.

In the table below, I have taken the rates directly from the Mayo Clinic Paper above (expressed per 100,000 population) and added another column (represented graphically as the green bar).  This additional column is the monthly incidence rate (PCR and antigen tests) in the State of Minnesota which, one would suppose would be a reasonable representation of the population seen at Mayo Clinic.

However, the population at Mayo Clinic seems to be quite different than the general population of Minn, at least until May.

For February, there were essentially no cases among study enrollees – vaccinated or unvaccinated.  For March and April, COVID-19 infections among unvaccinated study enrollees were 25%-50% less frequent than the general population.

By May, we see a pattern that looks like it might make sense. Unvaccinated case rates among study participants were essentially that of the general population (this is what we would expect) and rates among those with Moderna and Pfizer vaccines were significantly lower.  June is similar, with the Pfizer group having even fewer breakthrough infections than Moderna.

In July, however, something weird happens. Breakthrough infection rates among study enrollees who received Pfizer are identical to infection rates in Minnesota as a whole.  Unvaccinated study enrolled have almost twice the infection rate of the general population while those who received Moderna remain least affected.

So what can we conclude?  I would argue – not much.  The population sampled by Mayo Clinic really only resembles the population of Minnesota for the month of June.  It makes no sense that breakthrough infections among those receiving Pfizer would be equivalent to those in the general population (on July 15th, 52.9% of the Minnesota population was fully vaccinated).  So why would a study sample of 100% vaccinated Pfizer individuals have the same infection rate as a population with only 52.9% fully vaccinated?  Much of the trend of ‘vaccine failure’ in July is driven by this much much higher Pfizer rate (look across months at the red bar – July is far higher).

The authors note in their section on study limitations that the study cohort is “not demographically representative of the American population.”  I’d say that it isn’t representative of even the Minnesota population and would worry about ascertainment bias given the high rates of infection among Pfizer participants in July and zero infection in February.  Further, the authors note that while they see decreased effectiveness in July, this does not relate to the actual date when participants were vaccinated.

The vaccination effort in Minnesota peaked in April (link below) with a steep drop off since that time. Given such, as well as essentially no observations during February – the Mayo Clinic researchers simply do not have enough consistent data to tell a coherent story.  

Links: 

Click here
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15 August 2021: Update at Santa Monica Primary Care

Santa Monica Primary Care Update

 

 

Getting set up for a busy day of testing. 143 people scheduled for rapid antigen testing – making school return safer..

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13 August 2021 Blog Post: On Boosters

13 August 2021 Blog Post: On Boosters

Yesterday, August 12th 2021, the Food and Drug Administration “authorized” an extra vaccine dose for the Pfizer and Moderna mRNA vaccines for those who have received organ transplants (this had already been recommended) and “some people with weakened immune systems.” (link: https://www.washingtonpost.com/health/2021/08/12/booster-shot-coronavirus/).  The process by which these doses will be made available to the public is, theoretically, going to be worked out at a CDC meeting today, Friday the 13rd.  Not exactly an auspicious start.

So what were the FDA thinking and to whom do these recommendations for a booster apply?  

At its core, the Biden Administration seems to be folding under the relentless PR pressure generated by Pfizer suggesting a drop in vaccine efficacy (defined: degree to which a vaccine prevents disease, and possibly also transmission, under ideal and controlled circumstances – comparing a vaccinated group with a placebo group) over time.  Their paper, which has not undergone peer review, (link: https://www.medrxiv.org/content/10.1101/2021.07.28.21261159v1.full.pdf) shows robust vaccine efficacy at 6 months and concludes the following among 44,000 participants over age 16 and 2000 participants aged 12-15 (note that this study group received their vaccination as early as July 27th 2020 and as late as January 12th, 2021):

  1. Vaccine Efficacy against COVID-19 was 91% (95% CI 89.0‒93.2) through up to 6 months of follow-up
  2. Vaccine Efficacy of 86%‒100% was seen across countries and in populations with diverse characteristics of age, sex, race/ethnicity, and COVID-19 risk factors in participants without evidence of previous SARS-CoV-2 infection. 
  3. Vaccine Efficacy against severe disease was 97% (95% CI 80.3‒ 99.9). 
  4. In South Africa, where the SARS-CoV-2 variant of concern, B.1.351 (beta), was predominant, 100% (95% CI 53.5, 100.0) Vaccine Efficacy was observed. 

That sounds pretty good, right?  Considering that 18 months ago we would be doing backflips over a vaccine that had 50% (annual flu shot) to 70%, it seems that 91% at 6 months is excellent. For those interested in an excellent summary of vaccine efficacy, please refer to this WHO link:  https://www.who.int/news-room/feature-stories/detail/vaccine-efficacy-effectiveness-and-protection

The Biden Administration and the FDA are concentrating on this sentence in the referenced Pfizer paper:

“From its peak post-dose 2, observed Vaccine Efficacy (VE) declined. From 7 days to <2 months post-dose 2, VE was 96.2% (95% CI [93.3-98.1]); from 2 months to <4 months, VE was 90.1% (95% CI [86.6- 92.9]); and from 4 months to the data cut-off, VE was 83.7% (95% CI [74.7-89.9]).”

There are a ton of limitations to this observation, the first being that high not the least of which is a much wider confidence interval for the 83.7% estimate.  Notice that for the Vaccine Efficacy estimates from 7 days to 2 months that the 95% confidence interval is about 5 percentage points.  This is essentially the same (6 percentage points) for the 2 month to 4 month estimate.  However, for 4 months and beyond we are looking at a confidence range of 15% – meaning that the vaccine efficacy could be as high as 89.9%. Typically wide confidence intervals are due to fewer observations and, in fact, on careful inspection of the data (Figure 2; page 15) only 12,670 remain in the vaccinated group (started with 23,040) and 11,802 remain in the placebo group (started with 23.037).  Remember too, most of those who were in the placebo group have now been vaccinated.

The authors themselves note “preliminary analyses of breakthrough cases have not yet identified a correlate of protection, as vaccine protection rates remain high.”  Further, “early protection against COVID-19 without robust serum neutralization indicates that neutralizing titers alone do not appear to explain early BNT162b2- mediated protection from COVID-19. Other immune mechanisms (e.g., innate immune responses, CD4+ or CD8+ T-cell responses, B-cell memory responses, antibody-dependent cytotoxicity) may contribute to protection.”

Remember too in all of this – protection against severe disease remains at 97%.

A very fuzzy interpretation of these data are offered by Pfizer CEO Albert Bourla (who interestingly is a veterinarian with a PhD in Reproductive Biotechnology – so perhaps has good insight into ‘herd’ immunity):

“There is very good protection in the beginning, and then there’s waning. And when you come closer to six months, [waning] which is even more profound with delta [variant],” Pfizer chief executive Albert Bourla said. “The waning is … more profound for mild cases, but there is a clear waning also for hospitalizations and severe disease.”

I’m not sure which paper he is reading as the one offered has no data at 6 months (only greater than 4 months) and does not offer any subtype analysis when it comes to the delta variant, rather references only the South African (beta variant).

But practically, what does this mean? The FDA has linked their booster recommendation to those individuals with “a similar level of immune-system impairment” as those who have undergone organ transplants.  This should encompass about 2.7 percent of U.S. adults, according to the CDC, or about 7 million people, are immunocompromised. Some, like transplant patients, take immune-suppressing drugs to prevent organ rejection. Others have blood cancers and other illnesses that damage the immune system. Still others are on cancer chemotherapy.

As noted above, the CDC’s Advisory Committee on Immunization Practices is expected to vote to recommend the extra doses on Friday and to give further details on how they will be administered. The panel also is likely to urge patients to talk to their doctors about the additional shots – but without specific guidance from the CDC, it is unclear what advice doctors will offer.

 In reality, there is no process for ‘qualification’ or ‘authorization’ for a booster dose so really it will be left up to patients to self-identify.  Record keeping for boosters itself will be left to patients as, in California, there is no methodology to distinguish a third ‘booster’ dose from a routine first or second. There is no authorizing body, no prescription to be written. With a paper-based system, those coming in for a third booster will present themselves and be recorded as a new first dose – a process which will artificially inflate estimates of vaccine coverage across the state.

In the hopes of providing some quality control to this mixed up, poorly conceived and incompletely articulated effort, we at Santa Monica Primary Care have been using a quantitative measure for spike protein antibody (which is produced in response to the vaccine) as a guide. We have a small number of measurements so have a sense of where most folks pencil out in terms of quantitative vaccine response.  And, in fairness to Pfizer, we do see a decrease in antibody titers over time. Our goal, for those who may pursue a booster, is to have a level prior to a third shot and then a second measurement 2-3 weeks after the booster. However, the overwhelming majority of Americans should have a robust and sustainable protection with “only two” doses of the Pfizer or Moderna vaccines.

𝗦𝗶𝗴𝗻 𝗨𝗽 𝗳𝗼𝗿 𝗢𝘂𝗿 𝗡𝗲𝘄𝘀𝗹𝗲𝘁𝘁𝗲𝗿

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