Next-Generation COVID Vaccines Have Many Different Targets

 Vaccine developers are monitoring the durability of the immune response of current COVID vaccines while racing against variants to provide more options for protection, no matter what happens next in the pandemic.

Vaccine research, which used to be on the back burner, making only slow progress, has been fast-tracked in the past year, pushing the field of vaccinology forward, says Deborah Fuller, PhD, professor of microbiology and vaccine developer at the University of Washington School of Medicine in Seattle.

The emergence of dozens of vaccine candidates in less than a year has been nothing short of extraordinary, and "we're going to have an amazing toolbox to use to combat infectious disease for a long time to come," she says.

Booster shots are part of the plan to protect against COVID-19, but so are entirely new approaches to vaccines, including delivery routes that eliminate the need for injections, and easier storage to help ease vaccine supply shortages.

Supply-chain problems are the first major obstacles that teams like Fuller's are tackling. Anything that can break vaccines free of the so-called cold chain — the need for deep freezing or refrigeration — is a priority, she explains. The ability to store vaccines at room temperature would increase accessibility in parts of the world where cold storage is hard to come by.

The messenger (m)RNA vaccines, like the Pfizer and Moderna ones currently being used in the United States, are the most temperature-sensitive. "You can just look at a global map of where they're distributed and see which countries can accommodate the cold chain," says Fuller. Companies that produce the mRNA vaccines are working on different formulations to make the molecules stable at room temperature, she explains.

The vaccines that rely on viral vectors, such as those produced by Johnson & Johnson and AstraZeneca, "are stored at much nicer temperatures," says Anna Blakney, PhD, a vaccine developer and assistant professor in the Michael Smith Laboratories and the School of Biomedical Engineering, University of British Columbia, in Vancouver, Canada. Improvements in storage requirements across the board "will be here before we know it."

People who have received either of the two-shot mRNA vaccines might already be familiar with the common adverse effects of fatigue, arm pain, fever, aches, and chills, which are directly related to the mRNA in the vaccine, explains Blakney. "Being able to optimize the dose will cut down on side effects and presumably have the same efficacy."

Reducing Adverse Effects

The self-amplifying mRNA vaccines currently in development contain a lot of antigens to stimulate a strong immune response but have fewer infected cells. With less mRNA but an added replication protein, the molecule can make more copies of itself once it is inside the cell, with fewer adverse effects, says Blakney.

And with a strong immune response, a booster might not even be needed, Fuller adds.

As vaccination becomes more common and the threat of COVID-related death diminishes, one of the next priorities will be to minimize adverse effects. With an endemic virus circulating at low levels, "you're probably not willing to lose a day or two of work to suffer side effects," says Gregory Poland, MD, director of the Mayo Vaccine Research Group in Rochester, Minnesota.

And people might be able to avoid the needle entirely if some next-generation candidates get off the ground. At least seven non-injectable vaccines are in development, including a version of AstraZeneca's ChAdOx1 nCoV-19 (AZD1222).

Vaccines that could be delivered directly to the nose, for example, might confer mucosal protection, according to Fuller. Nasal vaccines don't have to be administered by a trained clinician and have the added advantage of inducing antibodies in the respiratory system to stop the virus before it gets a cellular foothold, she explains.

No Needles

Other groups are developing "swish-and-swallow" and pill-based vaccines, Poland reports.

"The beauty of this touches on the self-administered option," says Fuller. Imagine if people could have picked up self-administered vaccines in pharmacies early on in the pandemic. "We would have shut this thing down by now."

But despite the fast pace of COVID vaccine development, ongoing struggles in vaccine research programs remain and will likely create obstacles in coronavirus vaccine research.

A pan-virus vaccine — a "brass ring" in vaccine development — has been elusive for many infectious diseases, including influenza and HIV.

Some vaccinologists are trying to develop a meta-pan-virus vaccine that covers both influenza and coronaviruses, which would enable a single immunization to protect against both viruses, says Poland, who is working on vaccines for COVID-19.

Universal Vaccines

The high rates of morbidity, death, and long-term symptoms related to COVID-19 have pushed the search for a pan-coronavirus vaccine into high gear.

At the onset of the pandemic, "the house was on fire" so developers focused on the most expedient way to get vaccines out, says Poland. A focus on spike sequences from already circulating strains of COVID-19 was the fastest, most efficient approach.

Now researchers have time to look at pan-coronavirus candidates, and will rely on these narrow-target vaccines that can be updated to take on emerging variants.

The tricky part about pan-coronavirus vaccines, Fuller explains, is that they are "not something we're looking at next year, but probably a good 5 years down the line."

Even more difficult, she adds, is the identification of a part of the virus that won't mutate much but will still trigger an immune response. "The parts that are really vulnerable are poorly immunogenic, and the immune system can't 'see' them," so getting around this problem is "not trivial."

But the pace of vaccine development has accelerated during the pandemic and a first workable pan-virus vaccine is in sight.

A peptide-based version of a vaccine that targets several coronavirus antigens is being developed by Poland's team. And researchers are already testing a multivalent two-dose candidate at the Walter Reed Army Institute of Research. Their platform will allow add-ons of antigens from other coronaviruses to protect broadly and proactively against multiple coronavirus species and strains.

Researchers are also investigating the use of different combinations of vaccines to bolster an immune response with a cocktail of antigens. A trial of sequential immunization with Pfizer's mRNA-based vaccine and AstraZeneca's adenovirus-vectored version is underway in the United Kingdom. For mRNA vaccines, a cocktail could be built with multiple mRNA sequences that encode different bits of the virus, Blakney explains.

But how much protection is needed? "We don't know if there are certain thresholds of antibodies" that would be a marker of sufficient protection, she says. This is a strategy used for polio vaccines, and some clinical trial data already suggest that a target antibody level could be identified, she points out.

This threshold could also guide decision-making about boosters. "We don't know what level we need to meet, and the second dose increases your immunity so much," says Blakney. "There is a possibility that you'd only need one if you got to that antibody level" determined to be protective. "That would open up a lot of doors."

https://www.medscape.com/viewarticle/949501

Are COVID Boosters Really Inevitable?

 When Pfizer CEO Albert Bourla said people will likely need a COVID vaccine booster in 6 to 12 months, and that annual vaccines were possible, public health and infectious disease experts were quick to put on the brakes.

There aren't enough data yet to make that call, said Paul Offit, MD, a vaccine expert at Children's Hospital of Philadelphia.

"We'll have a better idea in about 1 year," Offit told MedPage Today.

Experts have said they do believe it's likely that boosters will eventually be necessary. When that will be, how often they'll be needed, and whether that will vary by vaccine brand, or by differences in immune response, is still anyone's guess.

"I fully believe we are going to need boosters," said Robert Schooley, MD, an infectious disease expert at the University of California San Diego. "It may be that we need to vaccinate more frequently if, over time, we have a less vigorous immune response. It may be that vaccines with potent immunity like the mRNA vaccines will need to be boosted less frequently than other vaccines using other platforms."

"It may be that how soon we need to be revaccinated depends on how the virus evolves in terms of its ability to evade current vaccines," he added. "These are all unknowns right now."

Why is Schooley so certain that boosters will be a necessity? For one, breakthrough infections, while rare, have occurred after vaccination. Reinfections also have occurred, even though they appear to be less common -- though their true rate remains unknown. The four other coronaviruses that regularly circulate through the population are able to reinfect people, so "there's no reason to expect this will be different," Schooley said.

While two other human coronaviruses, MERS and the first SARS, have shown a long-standing immune response in lab studies, these "don't show if when you're re-exposed, whether you get sick," he said. "That's where the rubber hits the road."

"Measuring something in the lab is reassuring but not definitive," he added. "We don't know for sure about SARS and MERS because these viruses aren't circulating and people aren't regularly re-exposed."

In addition, leaving large swaths of the globe unvaccinated is sure to breed new variants that could evade vaccines, he said. "If we continue to let this virus replicate in large pockets of the world, we can expect it to come back in an evolved form and require revaccination."

Given all the uncertainty, Schooley said researchers are closely monitoring several factors to better judge the need for boosters. This includes coming to a better understanding of immune responses following vaccination.

"We don't yet know what parameters are most important in reinfection," he said. "We study neutralizing antibodies because they're easy, but it may be that cell-mediated responses are more important. We don't completely understand the lab parameters that are key in telling us who needs to be revaccinated."

The other element is monitoring reinfections, he said. "As we get a better idea about when reinfections occur and whether they're accelerating in terms of frequency, we can do a mathematical model and figure out the risk/benefit ratio for going ahead with a booster."

Schooley said monitoring systems will likely reveal an uptick in mild disease as immunity begins to wane. "We won't see people in the ICU and dying," he said. "When the tempo of symptomatic but not severe illness picks up, we can get ahead of that with vaccination."

That's why it's so critical to have boosters at the ready, he said. "We can nip it in the bud with a vaccine that's been tweaked to focus on the variants circulating at the time."

Vaccine makers are already preparing for that likelihood. Pfizer is studying the efficacy of a third dose of its vaccine given 6 to 12 months after the initial two doses, as well as a new version tailored to the B.1.351, or "South African," variant. Moderna is conducting a similar program that is testing a third dose and an updated shot targeted to B.1.351.

So far, both vaccines have reported good efficacy at the 6-month mark, at 91.3% for Pfizer and 90% for Moderna, with higher rates for protecting against severe illness and death. But that's no reason to relax, Schooley said.

"The important thing is to be vigilant and act on what we see," he said, "rather than stumbling into revaccination."

https://www.medpagetoday.com/special-reports/exclusives/92240

Lucira in full-court press on COVID with free pregame tests for some NBA ticketholders

 Only days after obtaining the FDA's blessing for its at-home COVID-19 test to be sold over the counter, Lucira Health has already initiated a full-court press on the virus.

The Bay Area company has signed on to provide its tests at no cost to NBA ticketholders heading to Golden State Warriors games, beginning with the team's April 23 tipoff against the Denver Nuggets and the public reopening of the Warriors’ Chase Center arena in San Francisco.

Attendees who purchase their tickets at least a week before each game will be eligible to receive Lucira’s single-use test. Use of the kit is voluntary, and is not needed for ticketholders who are already fully vaccinated.

The company's Check It kit includes a battery-powered testing device—a potential piece of pandemic memorabilia—to process nasal swab samples. The device returns results within 30 minutes, with positive results delivered in as quickly as 11 minutes.

Users can submit an included code via text message to receive a digital copy of their results, called a LUCI Pass, and to automatically submit the results to public health agencies.

Once ticketholders complete the test at home, they’ll be asked to link their LUCI Pass to Clear’s Health Pass portal; Clear recently partnered with the NBA to streamline health status verification at the doors of the league’s participating arenas, including the Chase Center.

The Warriors’ partnership with Lucira will make it easier for fans to comply with the California Department of Public Health’s mandate that all entrants to the state’s arenas provide proof of a full vaccination or a negative COVID test taken within 48 hours of tipoff.

Lucira and the Warriors first piloted their partnership at the team’s April 19 away game against the Philadelphia 76ers, CEO Erik Engelson said in a release.

“Numerous COVID-19 studies have proven testing improves safety and health, especially with large public gatherings. No over-the-counter test has Lucira’s PCR-quality accuracy in such an easy-to-use form,” Engelson said.

The test, which has demonstrated an accuracy rate of about 98%, became in November the first at-home COVID-19 diagnostic greenlighted by the FDA. At the time, it was only allowed to be used in clinical settings and prescribed by healthcare providers for self-testing at home.

However, earlier this month the FDA authorized the Check It test for over-the-counter purchases. Individuals with or without symptoms of the virus can now order the testing kit on Lucira's website for $55.

The company is counting on the OTC authorization to boost its sales after seeing its growth “hampered” by increased vaccinations and a slowdown in COVID testing in the U.S. over the first quarter of the year, Engelson said in a statement.

Ahead of the May 13 release of its full first-quarter financials, the company shared that it expects net revenues for the period to fall somewhere between $4 million and $4.5 million. This is the first quarter for which Lucira is publicly releasing its results, after the company closed an almost $176 million IPO in February.

https://www.fiercebiotech.com/medtech/lucira-health-sets-a-pick-covid-19-free-at-home-rapid-tests-for-some-nba-ticketholders

Who's hungry for M&A? Bristol Myers, Merck, Amgen and J&J: Moody's

 Forget the threat of increased antitrust scrutiny in the U.S. Drugmakers won’t let potential Federal Trade Commission (FTC) action get in the way of their deal-making, Moody's predicts—at least not yet.

That’s because drugmakers still need mergers and acquisitions to drive sales growth and strengthen their pipelines, Moody's analysts wrote in a new report.

Merck & Co., Amgen, Johnson & Johnson and Bristol Myers Squibb are the most likely U.S. buyers, the analysts figure, based on the portfolio challenges each company faces, their financial standing and their public comments about acquisition plans.

That’s not to say Moody’s envisions any megamergers from these companies. Instead, the analysts foresee “a continuation of pipeline-stage deals, or those involving products just recently approved,” the report states. The FTC’s recent announcement of a working group to reevaluate its practices in reviewing pharma M&A spells trouble for the industry and could discourage large acquisitions, Moody’s said.

Among the 10 large U.S. drugmakers Moody’s follows, Merck has the most financial firepower to pull off M&A without hurting its current credit rating. Merck’s cash on hand, existing debt level and potential free cash flow together look the best among its peers.

The New Jersey pharma has been under investor pressure to diversify its portfolio beyond what’s soon to be the world’s best-selling drug—its immuno-oncology therapy Keytruda. The company did strike several deals recently when incoming CEO Rob Davis was behind the M&A wheel as chief financial officer. It unveiled just two months ago a $1.85 billion transaction for Pandion Therapeutics.

During the company’s fourth-quarter earnings call, Davis said the company would still be looking at “smaller opportunities where we can find great science earlier in its life” and will not rule out larger-scale deals.

While Merck has been doing relatively small transactions, Bristol Myers recently folded in Celgene in a $74 billion takeover and bought MyoKardia for $13.1 billion. Nevertheless, Moody’s still thinks the company could reach for its M&A wallet again.

Bristol Myers CEO Giovanni Caforio just touted his company’s “significant financial flexibility” for doing deals at this year’s annual J.P. Morgan healthcare conference in January and labeled business development a “top priority.”

Midsize bolt-on deals that can drive long-term growth in the second half of the 2020s will be the company’s focus, Caforio said. Moody’s estimates the New York pharma has “medium” capacity for M&A in its current A2 rating category.

As for Amgen, it recently bought immunology drug Otezla for $13.4 billion as part of a divestiture the FTC forced on Bristol Myers’ Celgene buy. This March alone, the California-based Big Biotech paid $1.9 billion for oncology player Five Prime Therapeutics and shelled out $55 million upfront for anti-inflammatory specialist Rodeo Therapeutics.

Currently among the California company’s top five drugs by 2020 sales, anti-inflammatory therapy Enbrel, bone meds Prolia and Xgeva, and neutropenia drug Neulasta are all either flat or declining. The fourth best-selling—and only fast-growing product—is Otezla, and it was bought into the portfolio rather than developed in-house.

Meanwhile, Johnson & Johnson was the buyer in a $6.5 billion deal for Momenta Pharmaceuticals last year. The company has one of the lowest debt levels in Big Pharma, with its debt ratio to EBITDA at 1.81x. Its cash and investments on hand, at $25.2 billion, is also the largest among the 10 firms on Moody’s list.

In contrast, AbbVie and Gilead Sciences ranked the lowest in terms of their M&A capacity. AbbVie is still in the process of digesting its humongous Allergan acquisition in 2020, and the Illinois pharma is targeting a debt reduction of $15 billion to $18 billion by the end of this year. Gilead also made several purchases recently, including its $21 billion deal for Immunomedics.

https://www.fiercepharma.com/pharma/bristol-myers-merck-amgen-j-j-are-most-likely-u-s-pharma-acquirers-moody-s

Next big COVID-19 bottleneck? A shortage of trained vaccine workers

 COVID-19 has put global manufacturing supply chains through the wringer: First, there were fears of a glass vial shortage; then, concerns cropped up about hold ups on plastic bags used to grow vaccine cells. Now, executives at a suite of COVID-19 heavyweights are raising flags about another pandemic resource in scarcity: people.

When Moderna last week revealed that its COVID-19 vaccine deliveries to countries like the U.K. and Canada would come in light, the mRNA player blamed the squeeze on limited “human and material resources." During a Friday summit on the pandemic vaccine scale-up, the biotech's CEO Stéphane Bancel offered some additional context: “The bottleneck right now is people.”

While Moderna handles the bulk of its manufacturing work in the U.S., the company's European supply chain depends upon Swiss CDMO Lonza, which has struggled to hire on enough specialized personnel for its vaccine production push, the chief executive said. 

"This is why there has been, in some countries, a little bit of delays in the past week or two," Bancel added. 

To fill the employment gap, Lonza is switching workers over from other projects at its Visp, Switzerland, plant and is hiring new staffers. The company has also reached out to other pharmas for help, "including companies on this panel," Bancel said, in a possible nod to GSK. 

It wouldn't be unfamiliar territory for the U.K. big pharma. As Glaxo plugs away on its own pair of vaccine hopefuls with Sanofi and Medicago, the company has recently lent its manufacturing muscle to production of Novavax's shot and CureVac's mRNA-based hopeful. 

The Moderna helmsman wasn't the only exec to flag the people shortage during the manufacturing summit, which featured experts from BIO, the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA), the Developing Countries Vaccine Manufacturers’ Network (DCVMN) and COVAX, plus GlaxoSmithKline, Bharat Biotech and Moderna.

Alongside material and export bottlenecks, "we have also seen, actually, the importance of the skilled workers you need," Thomas Cueni, director general of IFPMA, said. Leaders from GlaxoSmithKline, Bharat and Moderna had all raised similar concerns about shortages of trained vaccine workers, he noted.

According to a recent World Bank report, there should be enough vaccine doses worldwide to hit herd immunity by March 2022, but manufacturers have warned that that mission's success hinges on the resolution of trade barriers, export restrictions and the material shortages that ensue. 

Aside from the worker shortage, shortfalls of items viewed as "mundane" like single-use plastic bags have become a problem for Indian manufacturers, Rajinder Suri, the chief of DCVMN said.

"I don't think we have a solution in sight," he added.

Suri was among several at the panel, along with BIO chief Michelle McMurry-Heath, M.D., Ph.D., to raise concerns about the U.S.' recent invocation of the Defense Production Act, which has helped local companies shore up materials and equipment but also makes exporting supplies more difficult.

Bharat and SII and even Novavax have drawn attention to the plastic bag shortage in recent weeks, with SII chief Adar Poonawalla pleading with President Joe Biden on Twitter to ease exports coming out of the U.S.

https://www.fiercepharma.com/manufacturing/next-big-covid-19-bottleneck-a-shortage-trained-vaccine-workers-pharmas-and

Protara to conduct additional clinical study to support submission of Biologics License Application

 Protara Therapeutics, Inc. (Nasdaq: TARA), a clinical stage company developing transformative therapies for the treatment of cancer and rare diseases with significant unmet needs, today announced a path forward related to TARA-002 for the treatment of Lymphatic Malformations (LMs), which are rare malformations of the lymphatic vasculature for which there is no U.S. Food and Drug Administration (FDA)-approved treatment. Based on feedback from the FDA, the Company intends to complete confirmatory, large-scale, GMP manufacturing comparability in the second half of 2021 and subsequently initiate a clinical study in pediatric LM patients pending alignment with FDA on study design.

“With the benefit of the recent FDA feedback, we will work with the agency to align on a clinical study in pediatric LM patients, which, we believe, combined with the existing dataset for OK-432 (the originator compound for TARA-002), which demonstrated treatment effect and support for strong safety profile in over 500 LM patients, should provide a robust data package for this rare disease,” said Jesse Shefferman, Chief Executive Officer of Protara Therapeutics. “We have already begun preparation to initiate a clinical study in LMs and we look forward to continued collaboration with FDA to achieve our goal of delivering the first approved medication for LMs to these patients and their physicians.”

https://finance.yahoo.com/news/protara-therapeutics-provides-regulatory-tara-110000519.html

NY won’t say what it told DOJ about nursing home outbreaks

  Gov. Andrew Cuomo’s office said it won’t reveal what it told the U.S. Justice Department about COVID-19 outbreaks in nursing homes, partly because doing so would be an “invasion of personal privacy.”

The Justice Department last year asked the governors of several states, including New York, to turn over certain, basic statistics related to deaths and infections inside nursing homes.

That federal request, initially made in August and later expanded in October, followed reports by The Associated Press and other news organizations that the state’s official nursing home death toll was likely a significant undercount.

Cuomo’s began sending records to federal investigators last year. But his office has now denied a request from The Associated Press for copies of those documents.

Releasing the documents would “constitute an unwarranted invasion of personal privacy,” the governor’s records access officer, Jaclyn Clemmer, wrote in a letter dated April 15.

She didn’t explain whose privacy might be invaded, or how.

The public also isn’t entitled to see the records because they were “compiled for law enforcement purposes” and their disclosure would “interfere with law enforcement investigations,” Clemmer wrote.

Under state public records statutes, law enforcement agencies are allowed to withhold records related to ongoing criminal investigations. But in this case, the governor’s office has applied the exemption to data initially compiled for public health purposes which was sent to the Justice Department’s civil division.

In mid-February, Cuomo himself said he supported releasing the records.

“Look, I would have no problem with it,” said the governor, who as New York’s attorney general oversaw many complex criminal investigations. “I would have to have the lawyers talk to DOJ, but I would have no problem with it.”

New York is not the only state that has declined to make its response to Justice Department inquiries public.

A spokesperson for Pennsylvania Gov. Tom Wolf’s office said it could not provide a copy of its Sept. 9 response because the Justice Department hadn’t yet indicated it has “closed the investigation.”

New Jersey’s attorney general declined to comment.

Michigan provided The Associated Press with its Sept. 9, 2020, response to the Justice Department. It included information on deaths in state-run veterans homes and nursing homes run by counties.

In January, after a critical report by state Attorney General Letitia James, Cuomo’s office revealed that thousands more nursing home residents had died of COVID-19 than the state had previously reported.

Cuomo has since said it was a mistake to take so long to release the statistics, but he insisted the delay was not an attempt to obscure the death toll. The administration said it didn’t release a full tally sooner because it needed time to verify how many nursing home patients died after being transferred to hospitals.

The administration’s handling of the data is now the subject of an FBI investigation and an inquiry by the state Assembly, which is assessing whether there are grounds to impeach Cuomo.

The U.S. attorney’s office in Brooklyn, which is overseeing part of the federal inquiry, declined to comment.

In its document requests, the Justice Department asked for the number of residents, staff and visitors who contracted COVID-19 or died of the virus and the number of people admitted to each nursing home after being treated for COVID-19 at a hospital.

In his response, Michigan’s Chief Legal Counsel Mark Totten told the Justice Department he was concerned about the fairness of the investigation, which was aimed at states with governors who are Democrats.

“The U.S. Department of Justice has a long tradition of exercising its considerable power in an impartial and non-partisan manner and we are concerned your letter departs from that tradition,” Totten said.

https://apnews.com/article/ny-state-wire-health-coronavirus-government-and-politics-101ed7a6d8ef79f76c7d17d5c71e8650