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0108 One dose vs two
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The unfolding dosing controversy for COVID vaccines

Pressure is mounting to loosen up on the time between doses, but FDA is sticking to plan A

Pressure is mounting to loosen up on the time between doses, but FDA is sticking to plan A.

The one dose versus two controversy for COVID vaccines has a few twists left, with the incoming Biden administration departing from FDA’s conservatism in favor of giving more people their first shot sooner. While FDA is digging its heels in, it’s becoming more of a lone voice as more countries consider the raging pandemic an emergency worth breaking the glass for. 

The Biden administration will not continue Operation Warp Speed’s policy of holding a second dose in reserve. It may hold some back, but the ratio will not be close to the one-to-one ratio of distributed-to-reserved vaccine that is the current policy, two sources who have been briefed by the Biden transition team told BioCentury.

Biden’s team is confident that manufacturing will keep up with demand for second doses, according to the sources, who wished not be named.

The position is in direct contrast to FDA’s announcement earlier this week that it would not bend from the authorized dosing schedules to stretch vaccine supplies further. 

In a Friday briefing with reporters, FDA Commissioner Stephen Hahn reiterated the agency’s opposition to experimenting with single- or half-doses of vaccines that have been authorized in two-dose regimens. Other countries and the WHO this week indicated they are changing the dosing regimen to get the first dose to more people, or thinking of doing so.

The controversy sees scientific orthodoxy pitted against the urgency of the moment, layered on the orthogonal dilemma of retaining the public’s confidence in vaccines versus expanding protection across the population as fast as possible.

The issue is whether to only allow for use of regimens that have been proven safe and effective in clinical trials, as FDA believes, or whether to alter them to maximize the number of people who can obtain some level of immunity, either by stretching the interval between doses or by using lower doses than those authorized.

The agency’s concern with any deviation is that people will assume they are fully immunized when they are not, and that it runs a “significant risk of placing public health at risk,” according to the statement issued by Hahn and Center for Biologics Evaluation and Research (CBER) Director Peter Marks.

Those in that camp worry that if immunity wanes after a single dose before the next one is administered, the result would be that the population doesn’t receive proper protection and the vaccine supplies are effectively wasted.

Biden’s team has discussed and rejected the idea of withholding second doses altogether, according to the two sources.

The main argument for stretching doses is to stem the escalation of new cases, in particular given the emergence of variants with higher transmissibility. Those in this camp argue the clinical trial data contain enough information to believe sufficient protection is gained from the first dose, and that if supplies aren’t ramped up to allow the second dose per schedule, the delay won’t significantly dent the level of immunity.

According to modeling from scientists at the University of Toronto and Stanford University, 23-29% of COVID-19 cases could be averted by a flexible strategy that holds 10% of supplies in reserve and administers 90% during the first three weeks, and 50% thereafter.

What the two camps agree on is that decisions are being made on the basis of insufficient data, in a race against time that demands policymakers make risk determinations under pressure that will affect vast numbers of people. 

However, it’s worth noting that the controversy doesn’t solve the major bottleneck in vaccinating the population. While the policy might double the number of people who could get vaccinated, the major problem at this point is deploying the vaccines that have already been distributed.

According to the CDC, 5.92 million people in the U.S. have received their first dose of vaccine, as of Jan. 7, less than 28% of the 21.4 million doses that were distributed. Globally, 18.6 million doses have been administered, according to data from the University of Oxford.

Deviation debate

Former FDA Commissioner Scott Gottlieb and Operation Warp Speed Chief Scientific Advisor Moncef Slaoui have both proposed deviations from the authorized schedule that would allow more doses to be administered, citing the gravity of the escalating case numbers in the pandemic.

Gottlieb has called FDA’s approach unnecessarily conservative, and has advocated for holding a small reserve of vaccines, while administering as many as possible as soon as possible.  His comments, made before the vaccine from Moderna Inc. (NASDAQ:MRNA) was authorized, were based on data from the clinical trial by Pfizer Inc. (NYSE:PFE) and BioNTech SE (NASDAQ:BNTX) indicating the first dose of Comirnaty (BNT162b2) is protective, coupled with confidence that Pfizer could manufacture sufficient doses to provide a second shot in time to meet the demand for the second vaccinations.

Slaoui has called for a different way to stretch supplies — halving the dose of the Moderna COVID-19 Vaccine (mRNA-1273). Slaoui cited Moderna’s clinical trial data showing that in individuals between the ages of 18 and 55, two doses of 50 μg elicited comparable immunity to two doses of 100 μg. Slaoui said Operation Warp Speed was in discussion with Moderna and FDA.

Phase IIa and Phase I data support the claim, based on neutralizing antibody titers. The 50 μg dose elicited 76% and 78% of the mean titers produced by the 100 μg dose in the two trials, respectively, at day 29, prior to the second dose. Those numbers rose to 100% and 84%, respectively, 28 days after the second dose. 

In their statement rebutting proposals to change policy, Hahn and Marks said FDA has been following discussions of these proposals, and suggestions of mixing and matching between different vaccines, but while they were “reasonable questions to consider and evaluate,” there was a risk to public health, and of misleading people about their level of protection.

They cited the Phase III trials on which the EUAs were based, in which 98% of participants for the Pfizer-BioNTech trial, and 92% of participants for the Moderna trial, received two doses, with three- and four-week intervals, respectively. The number of participants who received only one vaccine were followed for “a very short period of time,” meaning conclusions couldn’t be drawn “about the depth or duration of protection after a single dose of vaccine from the single dose percentages reported by the companies,” they wrote. 

The statement did not provide arguments against allowing half of the Moderna dose.

FDA out on a limb

FDA is at odds with policymakers in several other countries including the U.K., and with the WHO.

On Friday, WHO’s Strategic Advisory Group of Experts on Immunization (SAGE) issued interim guidance on the dosing of the Pfizer-BioNTech vaccine, endorsing the delay of a second vaccine for countries experiencing “exceptional epidemiological circumstances.” WHO recommended extending the interval beween doses to up to 42 days, though if additional clinical data on longer intervals become available it will revise the recommendation.

WHO looked at the data differently from FDA. It noted that efficacy started to show from day 12 after the first dose, and was about 89% between days 14 and 21, prior to the second dose. The intervals between doses ranged from 19 to 42 days. WHO also noted that neutralizing antibody responses were modest after the first dose and increased substantially after the second.

Source, FDA documents from the Vaccine and Related Biologicals Advisory Committee meeting, Dec. 10, 2020.

WHO’s website hosts a publication on vaccine immunology that states the standard two-dose schedule needs to occur at a minimum interval of three to four weeks, noting “longer intervals enhancing rather than reducing the responses,” to generate successive waves of primary B cell and germinal center responses.

In addition, some immunologists have argued that it can take about three weeks for T cell immunity to develop, extending the 21-day or 28-day intervals between doses of the COVID-19 vaccines would be unlikely to confer a significant risk, and that longer intervals could in fact improve outcomes.

The U.K.’s Joint Committee on Vaccination and Immunization published a statement Jan. 6 advising a maximum interval between the first and second doses of 12 weeks for both the Pfizer-BioNTech vaccine and COVID-19 Vaccine AstraZeneca (formerly AZD1222 ), the vaccine from AstraZeneca plc (LSE:AZN; NASDAQ:AZN) and the University of Oxford.

The JCVI concluded from the clinical data that the short-term protection from the first dose is very high from day 10 after vaccination. It cited efficacy data for the Pfizer-BioNTech vaccine of 52.4% between dose one and two, and stated that the timing of the cases that accrued in the Phase III study suggested most of the vaccine failures in the period between doses occurred shortly after vaccination. 

The U.K.’s MHRA authorized a two-dose regimen with a 4-12 week interval for COVID-19 Vaccine AstraZeneca. 

Several other countries are taking the same view. Denmark and Germany allow up to six weeks between doses for both Comirnaty and COVID-19 Vaccine Moderna for exceptional situations, and Belgium is considering altering the schedule though it has not yet done so.

Quebec’s Immunization Committee recommends giving the first dose to the largest number of people in its first six priority groups. It recommends then giving others in the population the first dose, unless efficacy studies indicate a decline in protection among the six priority groups, in which case they should be given the second dose. 

Source, FDA documents from the Vaccines and Related Biologicals Advisory Committee meeting, Dec. 17, 2020 

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