Only two weeks after the first experimental biologic for SARS-CoV-2 became available, the U.S. was more than 16 millions doses behind Operation Warp Speed’s goal of giving COVID-19 vaccines to 20 million people by the end of 2020.1 Responding to the slow rollout, Operation Warp Speed chief adviser Moncef Slaoui, MD proposed giving half-doses to speed up vaccination efforts.2 “We know [a 50-microgram dose] induces identical immune response to the 100-microgram dose, and therefore we are in discussion with Moderna and with the FDA,” Dr. Slaoui said.3 The call to cut vaccine doses in half in order to give more people a first dose of COVID-19 vaccine is opposed by the U.S. Food and Drug Administration (FDA), which cited lack of scientific evidence to support the change.4
As an alternative to cutting COVID-19 vaccine doses in half, there have been other proposals for giving more people a first dose. An op-ed in the The Washington Post on Jan. 3, 20215 called for delaying the administration of second doses of the vaccine in order to vaccinate more people with a first dose more quickly.
On Dec. 30, 2020, officials in the United Kingdom decided to delay the second dose to “within 12 weeks” of the first one as the best way to apportion a limited number of doses, despite “scant clinical evidence” that a 12-week gap will be as effective as a 21-day one.6 Other European countries are in the process of deciding whether to follow their lead,7 8 although the European Medicines Agency (EMA) has argued against the move, saying it departs from proven clinical trials.
Another idea for accelerating the rollout of different types of COVID-19 vaccines in the U.K. was made by the Joint Committee on Vaccination and Immunization. The committee suggested that in emergencies, a second dose of a different manufacturer’s vaccine might be used if the same manufacturer’s vaccine given as the first dose wasn’t available, or if it was unknown which type of vaccine was first administered.9
Two Experimental mRNA Vaccines Being Distributed in U.S. Under Emergency Use Authorization
In December 2020, the U.S. Food and Drug Administration (FDA) granted Emergency Use Authorization (EUA) to two experimental COVID-19 vaccines: Moderna’s mRNA-1273 and BioNTech and Pfizer’s BNT162b2, both of which are messenger RNA vaccines that are intended to be administered in two-shot regimens delivered intramuscularly three or four weeks apart. A statement released by the FDA on Jan. 4, 2021 noted…
Those participants who did not receive two vaccine doses at either a three-or four-week interval were generally only followed for a short period of time, such that we cannot conclude anything definitive about the depth or duration of protection after a single dose of vaccine from the single dose percentages reported by the companies.10
The Pfizer and Moderna COVID-19 vaccines are the first using mRNA technology, and the companies did not study extended dosing schedules. Pfizer has objected to the proposal that the vaccine be used with a longer interval time between vaccinations.11
Second Doses of COVID-19 Vaccine Held in Reserve
Due to concerns about manufacturing and supply chain issues, the federal government and some hospitals have held back vaccine doses to ensure those who have received the first shot will have guaranteed access to the second. Currently, the government is holding back more than half of the vaccine inventory for second doses. However, both Pfizer and Moderna are ramping up their vaccine production.12 13
FDA Claims Dosing and Schedule Changes Not Anchored by Evidence
Nobody knows for sure how effective a single dose of COVID-19 vaccine will be in preventing moderate to severe COVID-19 disease or for how long, given that clinical trials were set up to test a two-dose schedule. Furthermore, health officials are concerned that giving people half doses or only one dose of the vaccine or delaying administration of the second dose could increase the chance of the virus evolving to resist any effect of the vaccines.14
FDA chief Stephen Hahn and agency vaccine center director Peter Marks rebuffed any changes to the current plan in a statement, saying, “at this time, suggesting changes to the FDA-authorized dosing or schedules of these vaccines is premature and not rooted solidly in the available evidence… Making such changes that are not supported by adequate scientific evidence may ultimately be counterproductive to public health.”15
“A Risky Venture” To Change Dosing or Schedules for COVID-19 Vaccinations
“I understand some of the rationale to do this, but again, it’s not really data driven,” said Norman Baylor, PhD, former FDA director. “It’s a very risky venture because if it fails, you’re in worse shape.”
Dr. Baylor, who previously headed the FDA’s Center for Biologics Evaluation and Research, further elaborated that there isn’t enough data to fully whether administering just one dose or delaying administration of a prolonged second dose of COVID-19 vaccines will prevent moderate to severe COVID-19 disease. While more people would receive a vaccination by increasing the time between the administration of both doses, the outcome may be different from what the clinical trials suggested.16
STAT described the move in the U.K. to change dosing schedules as “effectively turning [the U.K.] into a living laboratory.” The U.S. news outlet accused the U.K. of basing its new vaccination schedule “on small slices of evidence mined from ‘subsets of subsets’ of participants in clinical trials… and on general principles of vaccinology rather than on actual research into the specific vaccines being used.” It added…
If the efforts succeed, the world will have learnt a great deal. If they fail, the world will also have gained important information, though some fear it could come at a high cost.17
Could a Gap Between Doses Lead to Vaccine Resistant Strains of SARS-CoV-2?
Paul Bieniasz, PhD, a retrovirologist from Rockefeller University, is watching the dosing debate with dread. Dr. Bieniasz, who is studying how the SARS-CoV-2 virus can acquire mutations, has warned that the U.K. was taking a gamble that risked fostering vaccine resistant forms of the virus.”18 He told STAT…
My concern, as a virologist, is that if you wanted to make a vaccine-resistant strain, what you would do is to build a cohort of partially immunized individuals in the teeth of a highly prevalent viral infection.19
Collecting Safety Data Difficult When Vaccines Interchanged
Several researchers have noted that it is far from certain that the vaccines are interchangeable “None of this is being data driven right now,” said Phyllis Tien, MD, an infectious disease physician at the University of California, San Francisco. “We’re kind of in this Wild West.”20
Swapping out one manufacturer’s vaccine for another by allowing different COVID-19 vaccines to be used interchangeably for the first and second doses may still help protect against COVID-19 disease, but it remains a scientific gamble. With different ingredients in each vaccine, there are many outstanding questions about the hybrid vaccination approach.21
Click here to view References:
1 LaVito A. Sluggish Vaccine Campaign Raises Specter of U.S. Dysfunction. Bloomberg Dec. 30, 2020.
2 Ehley B. Feds may cut Moderna vaccine doses in half so more people get shots, Warp Speed adviser says. Politico Jan. 3, 2021.
3 Lee J. Slaoui proposes half-doses of Modern’s COVID-19 vaccine to speed vaccinations. Market Watch Jan. 4, 2021.
4 Vergano D. A. Slow Start to COVID-19 Vaccines Has The FDA Facing Calls To Change Shot Schedules. Buzzfeed News Jan. 7, 2021.
5 Wachter R, Jha A. It’s time to consider delaying the second dose of coronavirus vaccine. The Washington Post Jan. 3, 2021.
6 Dunn K, Kahn J. The U.K. is delaying the second dose of COVID vaccines to 12 weeks. Is that even safe? Fortune Jan. 12, 2021.
7 McKie R. Why is Britain delaying second doses of Covid vaccines? The Guardian Jan. 3, 2021.
8 Hughes C. European countries delay giving second dose of COVID-19 vaccine. UPI Jan. 6, 2021.
9 Vergano D. A Slow Start to COVID-19 Vaccines Has The FDA Facing Calls To Change Shot Schedules. Buzzfeed News, Jan. 7, 2021.
10 Hahn S, Marks P. FDA Statement on Following the Authorized Dosing Schedules for COVID-19 Vaccines. FDA Jan. 4, 2021.
11 Branswell H. Britain takes a gamble with Covid-19 vaccines, upping the stakes for the rest of us STAT News Jan. 4, 2021.
12 Dai T, Yadav P. Why holding second doses of COVID-19 vaccines in reserve is the wrong strategy. USA Today Jan. 12, 2021.
13 Ehley B. Feds may cut Moderna vaccine doses in half so more people get shots, Warp Speed adviser says. Politico Jan. 3, 2021.
14 Vergano D. A Slow Start to COVID-19 Vaccines Has The FDA Facing Calls To Change Shot Schedules. Buzzfeed News Jan. 7, 2021.
16 Kelley A. ‘Very risky’ to delay second dose of COVID-19 vaccine, says former FDA director. The Hill Jan. 7, 2021.
17 Branswell H. Britain takes a gamble with Covid-19 vaccines, upping the stakes for the rest of us. STAT News Jan. 4, 2021.
18 Iacobucci G, Mahase E. Covid-19 vaccination: What’s the evidence for extending the dosing interval? The British Medical Journal Jan. 6, 2021; 372: n18.
19 Branswell H. Britain takes a gamble with Covid-19 vaccines, upping the stakes for the rest of us. STAT News Jan. 4, 2021.
20 Wu K. Britain Opens Door to Mix-and-Match Vaccinations, Worrying Experts The New York Times Jan. 1, 2021.