POST 133. February 23, 2021. CORONAVIRUS. “Going off your meds is a surefire way to aggravate your doctor. What if a whole country did it?” The United Kingdom has veered into uncharted territory by changing tack and introducing a revised COVID-19 vaccination protocol, one that involves distributing the second dose at 12 weeks, rather than the prescribed 21 days.”

“The U.K. will focus on giving as many people as possible a first dose of a coronavirus vaccine, even if this delays administering a second one, the government said Tuesday, despite a lack of data about the extent of the immunity conferred by a single dose.” (A)

“The U.K. will focus on giving as many people as possible a first dose of a coronavirus vaccine, even if this delays administering a second one, the government said Tuesday, despite a lack of data about the extent of the immunity conferred by a single dose.

The news comes as scientists in Europe are debating whether recipients should be given one dose instead of two given the scarcity of the vaccine, the difficulties in fending off a winter surge in infections, and a rapidly mounting death toll.

The problem: While scientists say a single dose may well confer sufficient immunity to stop the spread of the virus, there isn’t sufficient data confirming this because the clinical trials for available vaccines and those nearing authorizations were all designed around a two-dose regimen.

Britain, which is coming under severe strain amid the spread of a new, more infectious variant of the virus, is the first European government to change its policy. It stressed that vaccine recipients would still get a second dose, just three months later than planned.” (B)

The U.S. Food and Drug Administration has suggested Britain’s drug regulator may be gambling with public safety by expanding the time gap between administration of the first and second doses of Pfizer’s coronavirus vaccine beyond that proven safe and effective by trial data. The FDA warned in a statement on Monday that there was a “potential for harm” if people believed they were protected against COVID-19 by a first dose of Pfizer’s vaccine for longer than available data demonstrate.

Facing a dramatic surge in both infections and hospitalizations — fueled, according to U.K. officials, by a more infectious strain of the coronavirus discovered in southeast England — British officials decided last week to change their inoculation strategy…

Oxford scientists have said their trial data supports allowing a window of up to 12 weeks between shots, and that their vaccine will provide protection to the full extent possible (up to 74% effective at preventing symptomatic COVID-19 infection) for that full period.

Pfizer hasn’t said that, however. Along with its German partner BioNTech, the American pharmaceutical maker has made it clear that their trial data only shows efficacy for 21 days after a first dose.

The U.K. regulator appears to be making an assumption based on the available data from the Pfizer-BioNTech Phase 3 human trials…

“Suggesting changes to the FDA-authorized dosing or schedules of these vaccines is premature and not rooted solidly in the available evidence,” the U.S. agency said in its statement. “Without appropriate data supporting such changes in vaccine administration, we run a significant risk of placing public health at risk, undermining the historic vaccination efforts to protect the population from COVID-19.” (C)

The FDA has learned of reports that some health care facilities are trying to stretch the number of limited doses by cutting them in half, extending the length of time between doses, or mixing and matching vaccines in order to immunize more people against COVID-19.

The U.S. Food and Drug Administration is warning health care workers that any changes to the authorized dosing schedules of COVID-19 vaccines currently being administered will significantly place public health at risk and undermine “the historic vaccination effort to protect the population” from the coronavirus pandemic.

The first and second doses of the Pfizer-BioNTech vaccine are approved to be delivered within a 21-day window, while the Moderna injections should be spread over 28 days. When given at those intervals, both vaccines are about 95% effective, according to the respective drugmakers…

Officials added: “If people do not truly know how protective a vaccine is, there is the potential for harm because they may assume that they are fully protected when they are not and, accordingly, alter their behavior to take unnecessary risks.” (D)

“Other countries are studying the United Kingdom’s decision closely. There are reports that US president-elect Joe Biden’s COVID-19 advisers might recommend that the country provides the first dose of vaccine to as many people as possible, as quickly as possible. This strategy counts on projections that further supplies will arrive in time for boosters to be given on schedule…

Researchers, as well as scientific and medical advisers, should lose no time in monitoring the effects of a change to the dosing schedule so that any benefits or risks can quickly be factored into nations’ dosing strategies. This means following the effect on infections, and studying the duration of immunity in those who have received only one dose of a vaccine. Careful surveillance of coronavirus variants will also be required, to keep an eye out for the emergence of any that might weaken vaccine efficacy.

Scientists need to study any unintended consequences of the new strategy — for example, whether, during a lengthy gap between doses, people are more likely to begin resuming pre-pandemic lifestyles, which they should not be doing. It will also be important to study the effect on public trust in vaccination after a sudden change to regulatory guidance. Regulators and scientific advisers need to be ready to be transparent about those consequences with the rest of the world. At the same time, if the strategy works well, then relevant insights should be passed on so that others can benefit.

Ultimately, there should be enough vaccine supplies to go round, so, in the long term, there will be no need to lengthen the gap between doses. But until there are sufficient supplies, scientific advice must be based on published and easily accessible evidence. It’s an essential principle of the science–government relationship.

The United Kingdom’s strategy has been widely reported worldwide, and other countries are considering whether it is both safe and efficacious to recommend this approach as more vaccines are rolled out. Transparency is essential for safety and efficacy — and for public confidence, particularly given that relatively large numbers of people are hesitant about receiving vaccines.” (E)

“What are the risks of spacing out doses?

They’re medical, theoretical and social. The medical risk is that the first dose almost certainly won’t be as protective as two doses. Spacing out doses extends the period when people — most of whom have been chosen to get vaccines quickly at this point for reasons of vulnerability — will have suboptimal protection until they get their second dose. The theoretical risk is that a weak response to the virus in millions of people who have received just one dose would foster the emergence of new variants that could evade vaccine-induced antibodies. This would undermine a year’s work to develop safe and effective vaccines. The social risk is that mixed messages on the topic — from governments, regulators, professional groups and drugmakers — will make it more difficult to communicate with the public on vaccines that are already controversial, and shunned by some. There is also concern that inoculated patients may change their behavior in a way that increases the risk of spread, negating some of the benefits of vaccination.

What do others say?

Although AstraZeneca has been in favor of spacing out shots, Moderna and Pfizer have been more cautious. Pfizer said the safety and efficacy of its vaccine hasn’t been evaluated on different dosing schedules, and that it’s critical that health authorities carefully monitor the effects of any alternative regimens and ensure each recipient is afforded the maximum possible protection, “which means immunization with two doses of the vaccine.” Anthony Fauci, who heads the U.S. National Institute of Allergy and Infectious Diseases, said he’s worried about the push to stretch dosing schedules. The British Medical Association called for the U.K. to “urgently review” its decision to allow delays of the Pfizer-BioNTech vaccine. The U.K. physicians group supports delays of up to six weeks, but said Britain’s plan goes “well beyond” that.” (F)

“The European Medicines Agency (EMA), no longer responsible for the United Kingdom since Brexit, is skeptical of the decision. A maximum limit for the time interval between doses of the BioNTech-Pfizer vaccine is not explicitly defined, but the proof of efficiency is based on a study in which the doses were administered 19 to 42 days apart, according to EMA. Administration of the second dose after a six-month interval, for instance, would not comply with the regulations and would require an amendment to the authorization and more clinical data, the agency said….

The World Health Organization  (WHO), however, believes that delaying the second dose of the BioNTech-Pfizer vaccine is an option. In exceptional cases, extending the time between the two shots by a couple of weeks would be possible, the chair of the WHO’s Strategic Advisory Group of Experts on Immunization (SAGE), Alejandro Cravioto, told journalists.

Thomas Mertens, chairman of the Permanent Vaccination Commission (STIKO) at Germany’s public health agency, the Robert Koch Institute, also takes a positive view of the British plan. “Since the interval between the two vaccinations can very likely vary within wide limits and protection is already very good after one shot, it is certainly worth considering giving preference to the first injection in the event of a vaccine shortage,” he said.”  (G)

“The Centers for Disease Control and Prevention has quietly changed its recommendations for coronavirus immunizations to give doctors the flexibility to handle “exceptional circumstances,” a spokeswoman said, even though the changes have not been studied in large clinical trials.

In guidelines posted on the agency’s website on Thursday, the C.D.C. said that patients may switch between the two authorized vaccines — one by Pfizer and BioNTech, the other by Moderna — between the first and second doses in “exceptional situations.” The C.D.C. also said patients may extend the interval between doses to six weeks from three or four if giving the second dose sooner was “not feasible.”

With the possibility of vaccine shortages on the horizon and little expectation that supply can be increased before April, the changes may offer a way to vaccinate more people — a high priority for President Biden, who outlined his national coronavirus strategy on Thursday.

Until now, the C.D.C. had cautioned against any dosing changes, saying there was no evidence for it. A C.D.C. spokeswoman, Kristen Nordlund, said the agency’s “intention is not to suggest people do anything different, but provide clinicians with flexibility for exceptional circumstances.”

Dr. Anthony S. Fauci, the president’s special adviser for the coronavirus, had repeatedly advised against delaying the second dose or making any other changes in vaccination protocol without the data to support them. But on Friday, he seemed open to delaying second doses, at least for short periods, telling CNN he took no issue with the agency’s recommendations.

“What the C.D.C. is saying, sometimes, the situation is stressed where it’s very difficult to be exactly on time,” Dr. Fauci said. “So we’re saying, you can probably do it six weeks later, namely, two additional weeks. Quite frankly, immunologically, I don’t think that’s going to make a big difference.”..

The updated C.D.C. guidance still states that the authorized vaccines are “not interchangeable with each other or with other Covid-19 vaccine products.” The agency put the word “not” in bold on its website, and noted that the safety and efficacy of mixing doses has not been studied.

But “in exceptional situations in which the first-dose vaccine product cannot be determined or is no longer available,” the guidelines added, any available mRNA vaccine can be used for the second dose.

With respect to dosing, the guidance says that the second dose should be administered as close as possible to the recommended interval — three weeks for the Pfizer-BioNTech vaccine and four weeks for Moderna. But if that is “not feasible,” the agency wrote, the interval between doses may be extended to six weeks.

The pace of vaccination is critical not just to curbing disease and death, but also to heading off the effect of more infectious forms of the virus. The C.D.C. has warned that one variant, which is believed to be 50 percent more contagious, might become the dominant source of infection in the United States by March.

Although public health experts are optimistic that the existing vaccines will be effective against that variant, known as B.1.1.7, it may drive up the rate of new cases if enough people remain unvaccinated.” (H)

If people are only partially immunized with one dose, could that fuel more dangerous coronavirus variants?

That is a real concern, according to Paul Bieniasz, a retrovirologist at the Rockefeller University. Early in the pandemic, there was little pressure on the novel coronavirus to evolve because nobody’s immune system was primed against infection, and the microbe had easy pickings. But now millions of people have become infected and have developed antibodies, so mutations that give the virus a way to evade those defenses are rising to prominence. “The virus is going to evolve in response to antibodies, irrespective of how we administer vaccines,” Bieniasz says. “The question is: Would we be accelerating that evolution by creating country-sized populations of individuals with partial immunity?”

Just as not finishing your entire course of antibiotics could help to fuel antibiotic-resistant bacteria, not getting fully vaccinated could turn your body into a breeding ground for antibody-resistant viruses. But Trevor Bedford, a computational biologist at the Fred Hutchinson Cancer Research Center who tracks viral mutations, has tweeted that the pace of evolution is not only determined by the weakness or strength of the immune system. It is also affected by the sheer number of viruses circulating in the population, he wrote. Without widespread immunizations, the latter amount—and the number of variants that might beget a more formidable virus—will continue to grow.

Could a longer interval between first and second doses make a COVID vaccine more effective?

That result is possible. All COVID vaccines are not created equal, and the optimal dosing schedule depends on the specific design. Some vaccines are based on fragile strips of genetic material known as mRNA, some rely on hardier DNA, and others use protein fragments. These cores can be carried into a cell sheathed in a tiny lipid droplet or a harmless chimpanzee virus.” (I)

“The possibility that second doses could be delayed has some experts concerned because it might lead to millions of people walking around with only partial immunity to the coronavirus, a condition that could be ripe for harmful mutations of the virus to arise.

Delaying the second shot is a gamble, says Ramón Lorenzo-Redondo, a virologist at Northwestern University Feinberg School of Medicine in Chicago, particularly without a lot of evidence suggesting how well one dose works. Officials “shouldn’t gamble [their] best tools” to fight the pandemic, he says. “We don’t want to fuel [potential viral evolution] by doing suboptimal immunization of the population.”

How that fueling of virus evolution could happen comes down to the immune system. If people have full immunity as a result of vaccination, their immune response is likely to be robust, spawning large numbers of neutralizing antibodies, for example, that stop viruses from getting into cells and heading off harmful mutations before they arise. But if people have partial immunity, that immune response is likely to be weaker.

It’s like when doctors encourage patients to finish a full course of antibiotics, Lorenzo-Redondo says. In that case, eliminating susceptible bacteria with a full course could help lower the chance that stragglers build up resistance.

For the COVID-19 vaccine, if people’s second doses are delayed long enough — akin to not finishing a full complement of antibiotics — it’s possible that low numbers of neutralizing antibodies triggered by only one dose may only partially fight an infection. That might provide more time for variants of the virus with immune-dodging mutations to arise and thrive and be transmitted to other people.”  (J)

With shortages hitting vaccination sites from San Francisco to San Diego, news that Johnson and Johnson’s COVID-19 vaccine could win emergency authorization this week comes as a relief to health officials worried about the spread of dangerous new variants, and raises hopes there could be enough doses this spring to vaccinate anyone who wants a shot.

But is that a realistic timeline?

Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, and other health experts earlier this month said vaccines would be widely available to anyone as soon as April, though Fauci has since moved back his projection and said it could be late summer before most are inoculated. President Joe Biden last week said deals to secure 600 million doses of the Pfizer and Moderna vaccines by the end of July will provide enough for every American to get inoculated.

But some experts warn that it could be months before enough people get shots to have widespread herd immunity. And a closer look at the numbers suggests that, without speedier vaccine approvals or significant changes in how we’re vaccinating, that pessimism may be justified. Manufactured supply doesn’t necessarily track with getting it into people’s arms — there are logistical constraints — including shipping delays due to severe weather this week — and the unwillingness of many to get the shots.

The good news: The U.S. has picked up the vaccination pace, from averaging less than 1 million a day a month ago to about twice that now, according to the U.S. Centers for Disease Control and Prevention. That pace is likely to quicken as vaccines by Johnson and Johnson and other companies become available.

The bad news: Vaccination sites around the state are curtailing hours because they are running low on supply. Even Kaiser Permanente, one of the state’s largest HMOs, cannot provide shots to everyone who is qualified to have one. And emerging virus variants raise concerns that vaccines could be rendered less effective before enough people have had the shots to prevent outbreaks…

Dr. Ashish K. Jha, dean of the Brown University School of Public Health, said earlier this month that “sometime around April and May we will be in a situation where any American who wants a vaccine can get one.”

Doctors Scott Gottlieb of the American Enterprise Institute and Mark McClellan of Duke University’s health policy center, both former Food and Drug Administration commissioners, wrote earlier this month that health officials should prepare for a spring vaccine glut — and prepare a campaign to promote the vaccines’ safety.

“At some point, perhaps in April, supply will start exceeding demand,” they wrote in the Wall Street Journal earlier this month.

McClellan said Friday that nothing has altered his calculus on that.

“It is not that far off,” McClellan said. “It could be pretty soon when we get to the real challenge of making sure all those Americans who are unsure get the information they need to make a good decision.”

In the WSJ article McClellan and Gottlieb note that a Kaiser Family Foundation survey shows just under half of U.S. residents — 47% — say they want the COVID-19 vaccine, with the highest numbers among retirement-aged adults who are most at risk. Two-thirds of those 65 and older say they want to be vaccinated as soon as possible, while just 38% of adults under 30 say that…

Health experts are urging government officials to streamline approvals and get more shots into arms faster in a race against the evolving virus. Pfizer and Moderna last week noted a new study in the New England Journal of Medicine that questioned their vaccines’ effectiveness against the South African variant that has now been discovered in California.

“I am quite distressed about the ‘moving target’ that is happening from our political leaders right now about when enough supply will be available,” said Dr. Monica Gandhi, a medical professor at UC San Francisco.

Gandhi fears the country’s current vaccination pace won’t get shots to all who want them until September. She says government officials should speed emergency authorization of other vaccines in the pipeline and delay second doses of two-shot vaccines to allow more first-dose shots. That would offer at least some protection to more people, she said.

“At the current rate, we will not reach herd immunity until December,” Gandhi said, adding that her recommendations could speed that up by about four months.

“The only big concern I have about the whole thing is whether we’ll have adequate supply over the spring,” Hotez said. He noted that the AstraZeneca vaccine already has been approved for emergency use by the World Health Organization and European Medicines Agency.

“Getting the American people fully vaccinated by the fall, that was a good plan,” Hotez said. “The problem now is the U.K. variant. We need to accelerate that timetable.”” (K)

(A) The U.K. is delaying the second dose of COVID vaccines to 12 weeks. Is that even safe?, BY KATHERINE DUNN  AND JEREMY KAHN, https://fortune.com/2021/01/12/covid-vaccine-second-dose-uk-delay-coronavirus-vaccines/

(B) U.K. Delays Second Covid-19 Vaccine Dose as Europe Ponders How to Speed Up Immunization, By Bojan Pancevski, https://www.wsj.com/livecoverage/covid-2020-12-30/card/V5DP51QCAgFkVIfwcg2R

(C)FDA warns U.K. plan to delay 2nd doses of Pfizer vaccine could create “significant risk” to public health, BY TUCKER REALS, https://www.cbsnews.com/news/covid-vaccine-fda-united-kingdom-pfizer-dose-timing-significant-risk-public-health/

(D) FDA Warns Health Officials Not To Mess With COVID-19 Vaccine Doses Schedule, by Vanessa Romo, https://www.npr.org/sections/coronavirus-live-updates/2021/01/04/953431400/fda-warns-health-officials-not-to-mess-with-covid-19-vaccine-doses-schedule

(E) Science advisers: publish evidence behind COVID vaccine dosing strategy, https://www.nature.com/articles/d41586-021-00045-8

(F) Delay the Second Covid Vaccine Shot? What Experts Say, By John Lauerman and Jason Gale, https://www.bloomberg.com/news/articles/2021-01-25/why-delaying-the-second-covid-vaccine-shot-is-messy-quicktake

(G) Can the second dose of the COVID-19 vaccine be delayed?, https://www.dw.com/en/can-the-second-dose-of-the-covid-19-vaccine-be-delayed/a-56139676

(H) C.D.C. Eases Coronavirus Vaccine Rules for ‘Exceptional Circumstances’, by Sheryl Gay Stolberg, https://www.nytimes.com/2021/01/22/us/politics/cdc-coronavirus-vaccines.html?referringSource=articleShare

(I) Is It Safe to Delay a Second COVID Vaccine Dose?, By Marla Broadfoot, https://www.scientificamerican.com/article/is-it-safe-to-delay-a-second-covid-vaccine-dose/

(J)Could delaying a second vaccine dose lead to more dangerous coronavirus strains?, By Erin Garcia de Jesus, https://www.sciencenews.org/article/coronavirus-covid-19-vaccine-delay-second-dose-dangerous-strains

(K) Coronavirus: When will there be enough vaccine?, By JOHN WOOLFOLK, https://www.mercurynews.com/2021/02/21/coronavirus-when-will-there-be-enough-vaccine/

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