Take Another Look at Spacing Between COVID Vaccine Doses

 When most Americans showed up to get their first dose of an mRNA vaccine, they were sternly warned that they must schedule a second dose within a month. In my case, I politely explained that I would come back for my second dose at 3 months. The scheduler got flustered and treated me like I was a fugitive of the law. But a growing body of evidence over the last several months has shown that a longer interval provides better immunity in the long-term. It may even eliminate the need for a booster shot that's now being recommended.

In May, researchers at the University of Birmingham found that delaying the second Pfizer dose to 12 weeks after the first resulted in a 3.5 times greater antibody response in older people. The increase is likely even greater in a younger cohort. Hematologist Paul Moss, MBBS, PhD, a co-author of the study, concluded that it's a good idea to extend the time between the first and second doses of the vaccine. "An extended interval may help to sustain immunity against COVID-19 over the longer term and further improve the clinical efficacy of this powerful vaccine platform," he wrote.

Similarly, data showed delaying the second Oxford/AstraZeneca vaccine by 12 weeks resulted in a stronger antibody response. That became the U.K.'s recommendation, which not only conferred better immune protection but also enabled the U.K. to ration its limited vaccine supply in a way that saved more lives. It was a winning strategy.

The U.S. basis for designing the 2-dose regimen with a short interval was that the pandemic was raging and there was an urgency to getting the trial done quickly. It was also believed that a short interval could more rapidly address a spike in cases. Based on the thinking at the time, the short interval may have made sense. But some vaccinologists have pointed out that the two doses were so close together that they functioned as a single primer dose.

Given the current data, it appears that if we had spaced the two doses farther apart, we would have had two benefits: 1) We would have had more first doses on hand to protect Americans from January through March when we were supply constrained and 2) We might not be calling for boosters for the general population so quickly.

While we can't go back in time, we should consider where this growing body of data leaves us today.

Some may be concerned with studies showing that one dose is less effective than two doses against the Delta variant, even with the U.K.'s 12-week spacing approach. However, efficacy against simply infection is not the best endpoint. Instead, we need to look at death and hospitalizations.

Beyond only better immunity in the long-term, other considerations contribute to the present-day case for spacing the two doses. There are numerous anecdotal experiences suggesting that the typical vaccine side effects such as fatigue and malaise may be less common when the second dose is spaced at 3 months. The current short interval between vaccine doses may contribute to the rash of myocarditis cases we have seen in children. The heart complications are clustered after the second vaccine dose. (Incidentally, a Tel Aviv study found that a single dose of the Pfizer vaccine alone was 100% effective in children 12-15 years of age.) Such preliminary observations merit further study.

If the rigidity of the 3- and 4-week interval between doses represents one extreme, the other extreme is the lax guidance behind current booster recommendations. Time frames for booster shots are being suggested without any data to show when the vaccine protection against hospitalizations is waning. Anthony Fauci, MD, told CNN on Sunday that they are "aiming at around 8 months" after the second dose for a booster shot, "but there's flexibility on that and that's what we'll keep looking at." We need to show that same flexibility on the timing of the first two doses of the mRNA vaccine.

As the data are emerging, they are telling us to extend the original 3- and 4-week dosing interval. For me personally, I felt good about evidence to support waiting for my second dose until 3 months after my first. For people who have not yet received their second vaccine dose, let's use a data-driven approach to delay the second dose to 3 months. Doing so could yield more durable immune protection and may reduce the need for boosters.

Marty Makary MD, MPH, is editor-in-chief of MedPage Today as well as professor at the Johns Hopkins University School of Medicine and author of The Price We Pay: What Broke American Health Care -- and How to Fix It.

https://www.medpagetoday.com/opinion/marty-makary/94315

FDA Slaps Restrictions on JAK Inhibitors Over Serious Safety Risks

 The FDA has finished its review of a large postmarketing safety study of tofacitinib (Xeljanz, Xeljanz XR), and its conclusions do not bode well for the popular drug and the larger class of JAK inhibitors.

Data from the trial revealed increased risks for serious heart-related events -- including myocardial infarction (MI) and stroke -- as well as a higher risk for cancer, blood clots, and death. Even the lower 5-mg dose of tofacitinib turned up an increased risk of blood clots and death in the final analysis, the agency noted.

FDA is requiring new and updated warnings for tofacitinib, as well as two other arthritis medicines in the JAK inhibitor class -- baricitinib (Olumiant) and upadacitinib (Rinvoq). All three JAK inhibitors are approved for rheumatoid arthritis (alone or in combination), while tofacitinib is also approved in psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis.

"Since they share mechanisms of action with Xeljanz, FDA considers that these medicines may have similar risks," the agency said.

In the safety trial, tofacitinib was compared to tumor necrosis factor (TNF) blockers in rheumatoid arthritis patients also on methotrexate. Treatment with the JAK inhibitor was associated with an increased risk for major adverse cardiac events (MACE), including MI, cardiovascular death, and stroke (HR 1.33, 95% CI 0.91-1.94), which missed criteria for non-inferiority, as well as a higher risk for cancer (HR 1.48, 95% CI 1.04-2.09).

"To ensure the benefits of these three medicines outweigh the risks in patients who receive them, we are limiting all approved uses to certain patients who have not responded or cannot tolerate one or more TNF blockers," FDA said. "This is particularly the case in patients who are current or past smokers, those with other cardiovascular risk factors, those who develop a malignancy, and those with a known malignancy other than a successfully treated nonmelanoma skin cancer."

Notably, the restrictions will not apply to two JAK inhibitors used for certain blood disorders -- ruxolitinib (Jakafi) and fedratinib (Inrebic) -- as these are not indicated for arthritis and other inflammatory conditions.

https://www.medpagetoday.com/rheumatology/arthritis/94314

Two-thirds say COVID-19 situation is getting worse: Gallup

 Two-thirds of Americans say the coronavirus situation is getting worse as delta variant cases have overrun hospitals across the country, a new Gallup poll shows.

The poll found 68 percent of adults say the coronavirus situation is worsening, a significant reversal from June, when 89 percent of adults said they thought the coronavirus situation was getting better.

Currently, only 15 percent of respondents said they believe the coronavirus is getting better.

This is the third-lowest point for public confidence during the pandemic, after July 2020 and November.

There is a slight partisan divide in the results: 84 percent of Democrats believe the coronavirus situation is worsening, while only 51 percent of Republicans .

The increased fear of a worsening pandemic situation comes as vaccinations have slowed in the U.S. while the delta variant has caused a spike in infections nationwide.

Many states are seeing a strain on their hospitals, and some governors have begun calling in the National Guard and the Federal Emergency Management Agency for backup.

Currently, 39 percent of Americans are somewhat or very worried about catching the coronavirus, with 24 percent “completely” or “mostly” staying in their homes.

Masking is still the most popular mitigation, with 69 percent of individuals wearing a mask outside their home. 

The spike in cases caused the Centers for Disease Control and Prevention to reimplement recommendations for fully vaccinated individuals to wear masks indoors in areas with high COVID-19 transmission.

https://thehill.com/policy/healthcare/570324-two-thirds-say-covid-19-situation-is-getting-worse-gallup

California hits 80% level for covid vaccinations

 California on Tuesday surpassed the 80 percent threshold for residents ages 12 and older who have received at least one dose of the coronavirus vaccine, with officials urging those who have not yet gotten the shot to do so quickly to prevent further surges in cases and hospitalizations.

Gov. Gavin Newsom (D) announced the milestone in a press release, noting that California has “put more shots in arms than any other state.”

“We’ve made incredible progress vaccinating our population in a remarkably short amount of time, and our work continues to close the gap in our most impacted communities,” he added in a statement.

Newsom went on to argue that “getting vaccinated is the key to protecting against COVID-19 and the faster-spreading Delta variant.” 

“It’s how we end this thing,” he said. 

Newsom, who is facing a recall election later this month, has joined other California leaders to push for increased vaccinations by citing the Food and Drug Administration’s full approval of the Pfizer-BioNTech vaccine for Americans ages 16 and older.

The Pfizer vaccine is the first COVID-19 vaccine in the U.S. to move past an emergency use authorization. Those as young as 12 can also get the vaccine under the emergency authorization.

As of Tuesday, nearly 69 percent of California’s total population had received at least one COVID-19 shot, with about 56 percent fully vaccinated, according to the Centers for Disease Control and Prevention. 

Newsom also on Tuesday released his latest “On the Record” ethnic media column, in which he noted that “many of our most vulnerable communities where we are seeing low vaccination rates are targets of disinformation campaigns, which continue to put lives at risk, including our youngest children who are not yet eligible to receive the COVID-19 vaccine.” 

“Working with ethnic media, faith-based and community-based organizations, and many unique partners who are trusted messengers has been crucial to dispelling some of the most prevalent myths out there,” he added. 

“It’s time to fully embrace the facts that prove vaccines work, are safe, and are free – regardless of immigration status,” Newsom said. 

Last month, the governor announced that all state employees and health care workers would be required to either provide proof of vaccination or submit to weekly COVID-19 testing. 

California earlier this month also said it would be imposing a similar vaccination requirement for teachers and staff at public schools across the state, with Newsom calling it “a sustainable way of keeping schools open.” 

The state has also required all teachers and students to wear masks in schools, an issue which has resulted in legal battles in places like Texas and Florida, which have both imposed bans on school mask mandates.

https://thehill.com/policy/healthcare/570357-california-hits-80-percent-threshold-for-vaccinations

WHO investigating new COVID-19 variant named Mu

 The World Health Organization said it is monitoring another new COVID-19 variant with mutations that the agency fears could make it resistant to vaccines.

The Mu variant, also known as B.1.621, was added as a “variant of interest” to the organization’s watch list Monday.

“The Mu variant has a constellation of mutations that indicate potential properties of immune escape,” the bulletin said.

Preliminary data indicated that it may evade vaccines in a way similar to the Beta variant, but experts said more research on the strain is necessary.

Since first emerging in Colombia in January 2021, the Mu variant has popped up in at least 39 countries.

“Although the global prevalence of the Mu variant among sequenced cases has declined and is currently below 0.1%, the prevalence in Colombia (39%) and Ecuador

(13%) has consistently increased,” the agency said, though it added the uptick could be due to increased genetic sequencing.

The concerns over the new strain come as the highly contagious Delta variant has driven surges in cases across the globe.

https://nypost.com/2021/09/01/who-investigating-new-covid-19-variant-named-mu/

Lack of Vaccine Mandate a Competitive Edge in Hospital Staffing Wars

 In the rural northeastern corner of Missouri, Scotland County Hospital has been so low on staff that it sometimes had to turn away patients amid a surge in covid-19 cases.

The national covid staffing crunch means CEO Dr. Randy Tobler has hired more travel nurses to fill the gaps. And the prices are steep — what he called "crazy" rates of $200 an hour or more, which Tobler said his small rural hospital cannot afford.

A little over 60% of his staff is fully vaccinated. Even as covid cases rise, though, a vaccine mandate is out of the question.

"If that becomes our differential advantage, we probably won't have one until we're forced to have one," Tobler said. "Maybe that's the thing that will keep nurses here."

As of Thursday, about 39% of U.S. hospitals had announced vaccine mandates, said Colin Milligan, a spokesperson for the American Hospital Association. Across Missouri and the nation, hospitals are weighing more than patient and caregiver health in deciding whether to mandate covid vaccines for staffers.

The market for health care labor, strained by more than a year and a half of coping with the pandemic, continues to be pinched. While urban hospitals with deeper pockets for shoring up staff have implemented vaccine mandates, and may even use them as a selling point to recruit staffers and patients, their rural and regional counterparts are left with hard choices as cases surge again.

"Obviously, it's going to be a real challenge for these small, rural hospitals to mandate a vaccine when they're already facing such significant workforce shortages," said Alan Morgan, head of the National Rural Health Association.

Without vaccine mandates, this could lead to a desperate cycle: Areas with fewer vaccinated residents likely have fewer vaccinated hospital workers, too, making them more likely to be hard hit by the delta variant sweeping America. In the short term, mandates might drive away some workers. But the surge could also squeeze the hospital workforce further as patients flood in and staffers take sick days.

Rural covid mortality rates were almost 70% higher on average than urban ones for the week ending Aug. 15, according to the Rural Policy Research Institute.

Despite the scientific knowledge that covid vaccinations sharply lower the risk of infection, hospitalization and death, the lack of a vaccine mandate can serve as a hospital recruiting tool. In Nebraska, the state veterans affairs' agency prominently displays the lack of a vaccine requirement for nurses on its job site, The Associated Press reported.

It all comes back to workforce shortages, especially in more vaccine-hesitant communities, said Jacy Warrell, executive director of the Rural Health Association of Tennessee. She pointed out that some regional health care systems don't qualify for staffing assistance from the National Guard as they have fewer than 200 beds. A potential vaccine mandate further endangers their staffing numbers, she said.

"They're going to have to think twice about it," Warrell said. "They're going to have to weigh the risk and benefit there."

The mandates are having ripple effects throughout the health care industry. The federal government has mandated that all nursing homes require covid vaccinations or risk losing Medicare and Medicaid reimbursements, and industry groups have warned that workers may jump to other health care settings. Meanwhile, Montana has banned vaccine mandates altogether, and the Montana Hospital Association has gotten one call from a health care worker interested in working in the state because of it, said spokesperson Katy Peterson.

It's not just nurses at stake with vaccine mandates. Respiratory techs, nursing assistants, food service employees, billing staff and other health care workers are already in short supply. According to the latest KFF/The Washington Post Frontline Health Care Workers Survey, released in April, at least one-third of health care workers who assist with patient care and administrative tasks have considered leaving the workforce.

The combination of burnout and added stress of people leaving their jobs has worn down the health care workers the public often forgets about, said interventional radiology tech Joseph Brown, who works at Sutter Roseville Medical Center outside Sacramento, California.

This has a domino effect, Brown said: More of his co-workers are going on stress and medical leave as their numbers dwindle and while hospitals run out of beds. He said nurses' aides already doing backbreaking work are suddenly forced to care for more patients.

"Explain to me how you get 15 people up to a toilet, do the vitals, change the beds, provide the care you're supposed to provide for 15 people in an eight-hour shift and not injure yourself," he said.

In Missouri, Tobler said his wife, Heliene, is training to be a volunteer certified medical assistant to help fill the gap in the hospital's rural health clinic.

Tobler is waiting to see if the larger St. Louis hospitals lose staff in the coming weeks as their vaccine mandates go into effect, and what impact that could have throughout the state.

In the hard-hit southwestern corner of Missouri, CoxHealth president and CEO Steve Edwards said his health system headquartered in Springfield is upping its minimum wage to $15.25 an hour to compete for workers.

While the estimated $25 million price tag of such a salary boost will take away about half the hospital system's bottom line, Edwards said, the investment is necessary to keep up with the competitive labor market and cushion the blow of the potential loss of staffers to the hospital's upcoming Oct. 15 vaccine mandate.

"We're asking people to take bedpans and work all night and do really difficult work and maybe put themselves in harm's way," he said. "It seems like a much harder job than some of these 9-to-5 jobs in an Amazon distribution center."

Two of his employees died from covid. In July alone, Edwards said 500 staffers were out, predominantly due to the virus. The vaccine mandate could keep that from happening, Edwards said.

"You may have the finest neurosurgeon, but if you don't have a registration person everything stops," he said. "We're all interdependent on each other."

But California's Brown, who is vaccinated, said he worries about his colleagues who may lose their jobs because they are unwilling to comply with vaccine mandates.

California has mandated that health care workers complete their covid vaccination shots by the end of September. The state is already seeing traveling nurses turn down assignments there because they do not want to be vaccinated, CalMatters reported.

Since the mandate applies statewide, workers cannot go work at another hospital without vaccine requirements nearby. Brown is frustrated that hospital administrators and lawmakers, who have "zero covid exposure," are the ones making those decisions.

"Hospitals across the country posted signs that said 'Health care heroes work here.' Where is the reward for our heroes?" he asked. "Right now, the hospitals are telling us the reward for the heroes: 'If you don't get the vaccine, you're fired.'"

https://www.medscape.com/viewarticle/957868

US FDA approval tracker: August

 Fibrogen’s roxadustat received an expected FDA knockback last month after a negative panel in July. The FDA requested another study, but in the EU the outcome was wildly different, and full approval was granted eight days after the US disappointment. Two other US complete response letters were handed out, one for Spectrum’s Rolontis, owing to manufacturing issues, and the other for Sesen’s Vicineum. The regulators requested a whole new confirmatory trial for Sesen’s bladder cancer project, pushing a resubmission out to 2023. However, it was not all bad news last month as several approval decisions pegged for September came early. The most notable involved Ascendis’s growth hormone Skytofa, and Bristol Myers Squibb’s Opdivo for adjuvant treatment of high-risk urothelial carcinoma; the latter had been filed for muscle-invasive disease, based on the Checkmate-274 study, but the approved label makes no mention of this stipulation (Go or no go? A first for Nefecon, August 27, 2021).

Notable first-time US approval decisions in August
Project	Company	Indication(s)	2026e sales by indication ($m)	Outcome
Comirnaty	Pfizer/Biontech	Prevention of Covid-19 (aged 16 and older)	2,819	Full approval (still under EUA for ages 12-15)
Evrenzo (roxadustat)	Fibrogen/Astrazeneca/ Astellas	Anaemia in patients with chronic kidney disease on/not on dialysis	1,666	CRL (additional trial needed)
Skytrofa (Transcon hGH/ lonapegsomatropin)	Ascendis	Paediatric growth hormone deficiency	1,371	Approved (~1mth early)
AXS-05	Axsome	Major depressive disorder	1,277*	Delayed (no new date given)
Welireg (MK-6482/belzutifan)	Merck & Co	Von Hippel-Lindau disease-associated renal cancer	386	Approved (~1mth early)
Nexviazyme (avalglucosidase alfa)	Sanofi	Pompe disease	366	Approved
Korsuva injection	Cara/Vifor	Pruritis in haemodialysis patients	358	Approved
Rolontis	Spectrum	Neutropenia  in patients receiving myelosuppressive anti-cancer drugs	330	CRL (manufacturing, reinspection needed)
Vicineum	Sesen Bio	High risk BCG-unresponsive non-muscle invasive bladder cancer	292	CRL (CMC & new trial)
TicoVac	Pfizer	Tick-borne encephalitis	218	Approved
Topiramate oral solution	Eton	Tonic-clonic seizures, partial-onset seizures, and as preventative treatment of migraine	-	Extended to Nov 6
Epsolay	Sol-Gel	Papulopustular rosacea	-	No decision yet
*SBI not split out by depression type. Source: Evaluate Pharma & company releases.

 

Supplementary and other notable approval decisions in August
Product	Company	Indication (clinical trial)	Outcome
Jemperli	GSK/Anaptysbio	Adult patients with MMR-deficient recurrent or advanced solid tumours (Garnet)	Approved (accelerated)
Jardiance	Lilly/Boehringer	Heart failure with reduced ejection fraction (Emperor-Reduced)	Approved (~3wks early)
Opdivo	Bristol Myers Squibb	Adjuvant treatment for patients with high-risk urothelial carcinoma (Checkmate-274)	Approved (2wks early)
Xarelto	J&J	Peripheral artery disease patients post lower-extremity revascularisation (Voyager PAD)	Approved
Tibsovo	Servier	Previously treated, locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation (ClarIDHy)	Approved
Xywav	Jazz	Adult patients with idiopathic hypersomnia (NCT03533114)	Approved
Keytruda + Lenvima	Merck/Eisai	1L renal cell carcinoma (Clear/Keynote-581/Study 307)	Approved
Source: Evaluate Pharma & company releases.

 

Voluntarily withdrawn accelerated approvals
Product	Company	Withdrawn indication (clinical trials)
Istodax	Bristol Myers Squibb	2L peripheral T-cell lymphoma
Tecentriq (+ Abraxane)	Roche	PD-L1-positive, 1L triple-negative breast cancer (Impassion-130, Impassion-131)
Source: company releases. https://www.evaluate.com/vantage/articles/news/snippets/us-fda-approval-tracker-august-0