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From our Immunological Correspondent

A Shot in the Dark (1964) was the second movie in the Pink Panther series which launched Peter Sellers’s career as the bumbling French detective,  Inspector Clouseau.

By a strange quirk of fate, between February 22-24, 2023, two pivotal meetings to determine the future of RSV vaccines in pregnancy were held.

In Atlanta, Georgia, ACIP was debating the future of vaccines for RSV, with a view to advising the FDA on whether they should be licensed.

Meanwhile, 4,000 miles away in Lisbon, Portugal, the annual RSVVW meeting was being held at the lush five-star EPIC SANA Hotel. Conference fees were up to € 1065 – not including accommodation and travel. What would Greta say?

RSVVW? It is the annual conference for ReSVinet, the Dutch-based, industry sponsored, Respiratory Syncytial Virus Foundation. Not many of the 550 participants from 48 countries would be aware that the initials RSVVW disclose its aim: Respiratory Syncytial Virus – Vaccines for the World.

The Race

The background to this was the race to be first past the post with a RSV vaccine that would be given to every pregnant person in the world, to prevent their baby developing severe bronchiolitis. See Yellow and Other Virus and Vaccine Perils.

Attempts to make a vaccine for children never fully recovered from Pfizer’s disastrous experiment with formalin-inactivated RSV in 1966. Their “Lot 100” was responsible for several children developing Vaccine-Associated Enhanced Respiratory Disease (VAERD) – from which two died.

There was a three-horse race between Pfizer, GlaxoSmithKline (GSK) and Novavax to devise a vaccine to be given in pregnancy.

Novavax’s RSV vaccine ResVax fell at the first fence – it was ineffective. Pfizer’s MATISSE and GSK’s GRACE (Mat-009) trials were now neck and neck in the maternal phase 3 vaccine championship. Both had similar products – Pfizer’s was RSVpreF and GSK’s RSVpreF3. PreF refers to protein antigens from RSV viruses in the pre-fusion form.

Fall from GRACE

All had been going swimmingly with the GSK trial. Since November 2020 5,300 pregnant people had been enrolled of whom two thirds had received the active vaccine. Until the data monitoring committee spotted worrying data:

These results showed an obvious imbalance in the number of premature births and neonatal deaths in the vaccinated group. GSK, advised by their independent Data Monitoring Committee acted responsibly. They notified the regulatory bodies (FDA, MHRA, EMA etc.), stopped recruiting new participants and said that they notified all existing participants of this safety (= danger) signal. Where they were irresponsible is that they did not publicly disclose the reason for stopping the trial for twelve months.

Remarkably, there is evidence that investors quickly found out about the premature births and neonatal deaths. Steve Scala, of TD Cowen, an American multinational investment bank, asked about GSK’s analysis of the likely causes of these pre-term births at a conference on 7 March 2022.

Pfizer Clearly Ahead

With a walkover in sight, the Pfizer trial gathered momentum. As with their Covid Trials, there were problems at Ventavia where a couple of Pfizer sites were shut down for irregularities but this would not impede progress – See Boston Strangler.

In April 2022, Phase II results were promoted in the The New England Journal of Medicine (NEJM) which:

“employs a highly rigorous peer-review process to evaluate manuscripts for scientific accuracy, novelty, and importance.”

Rather the Phase II results, this paper was in fact Phase II Interim Analysis.  The final data looked somewhat different and are not in the journal.

At the same time that Peter Sellers was keeping us all in stitches, another UK comedian Eric Sykes, usually teamed up with his “sister” Hattie Jacques, who would plaintively cry “Oh Eric” at each demonstration of her brother’s ineptitude.

Oh Eric Phase I

Eric Rubin, Editor-in-Chief of the NEJM, dropped his guard when he allowed Pfizer’s promotion piece to be published.  The paper says:

“Fifteen of 403 infants (3.7%) across all the groups were born prematurely, most in the 36th week of gestation”.

The authors and ghosts and peer reviewers presumably omitted to point out that 14 of the 15 were in the vaccinated group, and further analysis showed that the mean incidence of preterm births in all the vaccinated was 4.3% compared with 1.3% in the placebo group.

Oh Eric Phase 2

Although Pfizer employee Kristen Friedman, or someone else, likely ghost-wrote the report, the lead author is pediatrician Prof Eric Simões, owner of Samshoma Medical Research Inc. and also employed by the University of Colorado.

Eric S had a foot in both camps, for at the same time that he was a Principal Investigator for Pfizer’s RSVpreF vaccine trial, he was a paid member of GSK’s Data Monitoring Committee for their RSVpreF3 trial!

He kept mum. The Phase II article contains no reference to the preterm births and neonatal deaths problem in GSK’s trial, a problem that Eric, you’d assume, knew all about.

Eric S also co-authored the latest Phase 3 Pfizer report (coincidentally also published in the NEJM) and again GSKgate is not referred to. Eric S probably wasn’t aware of Pfizer’s raw data; data that showed twice as many infants with “severe or life-threatening” neonatal jaundice in the vaccinated group, twice as many premature births before 34 weeks’ gestation, and showed that the vaccinated had a statistically significant excess of “severe or life-threatening” pre-eclampsia within one month of their shot.

Eric S’s papers in Eric R’s NEJM are curiously silent on breastfeeding. In 2011 Eric S wrote:

“The role of breast-feeding in preventing RSV disease and hospitalization for RSV is undisputed.”

He wrote this article in conjunction with Constanze Sommer, possibly a distant cousin of Peter Sellers’s glamorous co-star Elke Sommer.

Read all about it

There has been a recent epidemic of news items where journalists have shared portents of doom: the end of the world is nigh.

Of course readers of this blog will recall that the first RSV vaccines were created over 50 years ago.

Not a plug for Pfizer

The image above is taken from the website of the London School of Hygiene and Tropical Medicine (LSHTM) – a UK charity. Beate was the lead author of Pfizer’s Phase 3 trial to protect babies from the “potentially deadly” virus. She claims that the results were “absolutely excellent”.

Deadly, How deadly?

Not in the higher income countries where Pfizer hope the vaccine will be first approved. In 2016 the Gates foundation stumped up $M2.5 to establish a global mortality registry for respiratory syncytial virus to track vital information – RSV Gold – which seems to have given up on their task.

A recent journal article points out that in Finland, the number of RSV-related deaths extracted for the years 2000–2018 was too small to be shared due to the European Union’s GDPR. And in Scotland, with one of the higher mortality rates, 10 RSV-related deaths were identified in children under two years of age between 2010–2016. Most deaths are in children with severe underlying other conditions.  And the deaths occur at most at a rate of 69/100,000 hospitalizations.

Data manipulation.

Pfizer’s two presentations, at ACIP and RSVVW, were virtually identical.  Beate proclaimed the Good News in Lisbon while Pfizer’s Iona Munjal spread the Gospel at ACIP.

But one of Pfizer’s slides was missing at the Lisbon meeting.

How do you best display scary data about early preterm births? The starting point is the incidence: 20/3568 vs 11/3558. Put another way, an 81.8 percent increase in the vaccinated group. Greater than the success rate of preventing RSV disease in the babies. You must disguise it graphically.

This is where Inspector Clouseau’s magnifying glass comes in handy.

Can’t spot the problem? That’s the whole point. It’s the column on the very left that gives you the impression there is no problem.  But this is generated by 2 tricks.  One is the Y-Axis trick which shrinks smaller numbers down so they barely show against a huge axis.  The other is converting the numbers to percentages.

We have converted the Y axis to 250 units rather than 100 units, which should hide Pfizer’s problem even better but also converted the percentages back to numbers and now on the Left you see the problem they don’t want you to notice.

Beate’s Lisbon presentation didn’t show this slide.  But she was asked about prematurity by the chair, a BFG employee, philatelist and bon viveur Keith Klugman.   Looking down at her notes, she dashed off a quick answer about there being no statistically significant difference – and there was less prematurity overall than would be expected so participating in trials is good for people.

She didn’t mention that to participate you couldn’t have had a prior history of prematurity or any other problems in pregnancy.

The Klugman – Beate exchange looks stage-managed.

Before asked the question, Klugman said he was so thrilled with the results and excitedly announced that the Gates Foundation had given Pfizer a large donation ($27.5 million) to enable multidose vials of the RSVpreF vaccine to be manufactured for use in lower income countries.

This is a vaccine that does not yet have regulatory approval.

It has an adverse event profile that merits close examination.

It is not clear if it works in a meaningful sense.

There is no case for encouraging Western women to have it

Should Westerners decide whether it is used widely in Low or Middle Income Settings

The world of RSV prevention is dominated by doctors, who regularly get themselves tied up in knots trying not to say “pregnant women”.  Will this language work in Low and Middle Income settings?

The post A Shot in the Dark for Pregnant People first appeared on Dr. David Healy.

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