(CNN) Expect a bumpy ride this week when FDA advisers consider Covid-19 booster shots.

The two FDA scientists who intend to resign, Dr. Philip Krause and Marion Gruber, are authors on the Lancet article, Considerations in boosting COVID-19 vaccine immune responses, which details objections to the Biden booster plan.

Before we turn the microscope on this, two easy points:

• The Lancet authors, Paul Offit, et al., note that the vaccines, particularly Pfizer and Moderna, greatly exceed the anticipated protection. They use this to justify holding off on boosters. The original protection goal should not be considered acceptable, when better is possible.
• Offit has said he would want to see more serious outcomes, including death, to justify a booster. This is not callousness; there is a fear for the safety of more shots. Safety issues have not been observed with the Israeli Pfizer booster.  And Delta is bad to the bone. Enhanced mortality can be anticipated in advance of fact, without the human cost of waiting for the event.

Microscope. The authors fear increased vaccine reactions with a third dose, “such as myocarditis, which is more common after the second dose of some mRNA vaccines, or Guillain-Barre syndrome, which has been associated with adenovirus-vectored COVID-19 vaccines.”

The article modestly presents a meta-study of prior observational studies of vaccine effectiveness, with appropriate cautioning about the quality of these studies. The aggregate provides “a partial but useful snapshot of the changing situation, and some clear findings emerge.” In the main, that the aggregate of three vaccines is still effective against severe disease. Although there are breakout graphs, the presentation of an aggregate  statistic is troubling, since no one receives an aggregate vaccine. You get one of Pfizer, Moderna, or J&J.

In contradiction to Lancet doubts,  the Israeli study, BNT162b2 vaccine booster dose protection: A nationwide study from Israel , provides what many feel is high quality justification for a Pfizer booster.

Corona_two-dose-vaccination-data (Hebrew/English) is reference 11 of the Lancet paper, which picks a nit: “Of interest, reported effectiveness against severe disease in Israel was lower among people vaccinated either in January or April than in those vaccinated in February or March.” This discrepancy could be discounted by a variety of uncontrolled factors.

The Lancet article picks another nit with A nationwide study: “Mean follow-up was, however, only about 7 person-days (less than expected based on the apparent study design); perhaps more importantly, a very short-term protective effect would not necessarily imply worthwhile long-term benefit.” Rebuttal:

Every study is a synthesis of data. The Israeli study monitored a period of only 3 weeks, for two groups: those who received a booster in this time frame, and those who did not. It employs valid statistical techniques to get the result.  The Lancet authors prefer a less aggressive synthesis, entailing a longer study. Nevertheless, it is pretty convincing,  appropriate to the time-urgency of Delta.

The short study period of three weeks has an advantage. It reduces  the confounding effect of varying levels of COVID community presence, and seasonal factors. So it tends to isolate measurement of vaccine effectiveness. While studies that measure breakthrough over months use comparisons with the unvaccinated, a short study period is an extra bit of isolation.

The Lancet article objects to the use of antibody titers as proxies for immunity. “Even if humoral immunity appears to wane, reductions in neutralising antibody titre do not necessarily predict reductions in vaccine efficacy over time…” This has not yet been established as a fact for  COVID, so the objection is a form of professional judgement.

A booster can be justified in an entirely different way that has nothing to do with titers. (Medical News Today) Longer gap between COVID-19 vaccine doses may increase immune response. Quoting an AstraZenca study, “A gap of up to 45 weeks actually led to a stronger immune response compared with the recommended interval.” This is generally true for many immunizations. (CDC) Recommended and minimum ages and intervals between vaccine doses. A booster shot is plausible as an optimally timed second dose.

If details are too much, paradox. Israel conducted a national study with 1,144,690  participants. Although it is an observational study, the uniformity of the study environment approaches control. Israeli scientific culture is rigorous and critical. The Lancet article is based on a large number of less rigorous studies. For Pfizer, A nationwide study… overpowers Lancet.

So why the resistance? FDA/CDC are constituted to render decisions of the kind that A nationwide study… presents fact in the state of Israel. Nothing in the FDA/CDC charters permit rubber-stamping the authority of another national establishment, even one as competent as Israel.

Yet it might be the right course for Pfizer, the only subject of the Israeli study.  Two shots of Moderna, which has about 3X more mRNA than Pfizer, produce more durable immunity, so a booster is not quite as crucial. It depends on safety profile, which, it is to be hoped, is in process.

J&J is left to someone else.