Author: Staff Reporter

Seeking “additional clarifications” for a final “risk-benefit assessment” in order to grant emergency use listing (EUL) to Bharat Biotech’s Covid-19 vaccine, Covaxin, the technical advisory group (TAG) of the World Health Organisation (WHO) has held back approval for the indigenously developed vaccine, till at least one more week, if not longer. This, after the TAG convened on Tuesday specifically to discuss granting EUL to Covaxin.

The TAG — which is an independent advisory group that recommends to WHO on whether a Covid-19 vaccine fulfils criteria for EUL or not — will meet next on November 3.

This increases the uncertainty about the vaccination status of millions of people who received the two jabs of Covaxin as several regions, including North America and the European Union, only consider those people fully vaccinated who have received their full course of WHO-approved vaccines.

The WHO last week said that it “cannot cut corners” in granting EUL to the vaccine. It had also put the onus of the delay on Bharat Biotech, saying that the timeframe for granting EUL depends on how quickly a company can submit all the data required in order to evaluate the vaccine’s quality, safety, efficacy and its suitability for low- and middle-income countries.

The company, which has been submitting clinical trial data of its vaccine on a rolling basis to the WHO, had earlier in May said that it had applied for WHO’s EUL that was expected between July to September. Later in June, it claimed that it had held a “pre-submission” briefing with the world health body regarding EUL approval for Covaxin. Last month, in a statement, it said that “all data was submitted for EUL Application to WHO in early July.”

A pre-submission briefing provides an opportunity to the company to receive advice and guidance before submission of the final dossier, as well as an opportunity to meet WHO assessors who will be involved in examining their product. This implies that it should be held before submitting the application — and not after it.

Even earlier this month, the Strategic Advisory Group of Experts on Immunisation (SAGE) of the WHO had held back on giving EUL to Covaxin, which has demonstrated 77.8% efficacy against symptomatic Covid-19 and 65.2% efficacy against the Delta variant.

Millions of Americans are now eligible for Moderna and Johnson & Johnson booster shots and also they that they can choose a different company’s vaccine for that next shot, after the nation’s top public health official endorsed recommendations from expert advisers that the shots are safe and effective at bolstering protection against the coronavirus.

Certain people who received Pfizer vaccinations months ago already are eligible for a booster and now the Centers for Disease Control and Prevention says specific Moderna and Johnson & Johnson recipients qualify, too. And in a bigger change, the agency is allowing the flexibility of “mixing and matching” that extra dose regardless of which type people received first.

The green light on October 20^th from Rochelle Walensky, director of the Centers for Disease Control and Prevention, means that eligible Americans at risk of severe disease can choose any of the three boosters now authorized in the United States regardless of their original shot.

“The evidence shows that all three COVID-19 vaccines authorized in the United States are safe — as demonstrated by the over 400 million vaccine doses already given,” Walensky said in a statement Thursday night, several hours after receiving unanimous recommendations from the expert panel, called the Advisory Committee on Immunization Practices. “And, they are all highly effective in reducing the risk of severe disease, hospitalization, and death, even in the midst of the widely circulating delta variant.”

Walensky’s action — following authorization from federal regulators — largely fulfills the administration’s August pledge to make boosters of all three vaccines available to Americans, albeit a month later than promised and for a smaller group. The administration’s focus on boosters came as the highly contagious delta variant sickened millions and killed tens of thousands, and also reflected concern about waning immunity from the vaccines.

CDC’s sign-off on the additional boosters as well as the flexibility to mix and match the shots gives greater leeway to consumers, as well as to clinicians and pharmacies administering them to vulnerable populations. Health officials have repeatedly sought ways to make it easier for people to get a booster dose, especially those who have had side effects from one brand, or who worry about risks associated with a particular shot.

The availability of boosters will be particularly welcome to the 15 million recipients of the Johnson & Johnson vaccine, many of whom have been particularly fearful of breakthrough infections given that shot’s lower level of protection compared with the messenger RNA vaccines.

“I agree that those who received a [Johnson & Johnson] vaccine should receive a second dose — I would prefer that those individuals get an mRNA vaccine” rather than a second Johnson & Johnson shot, said advisory panel member Pablo J. Sanchez, a pediatrician at Ohio State University.

Interchangeability of shots is also likely to speed booster vaccination in nursing homes and other institutional settings where residents received different shots during the early rollout. The Pfizer-BioNTech booster is already in use since it was authorized and recommended last month.

“I think the opportunity for these [mix and match] boosts [is] priceless,” said Helen Keipp Talbot, an infectious-disease doctor at Vanderbilt University and panel member.

The CDC plans to release guidance early next week with more detailed information about who might benefit from choosing one booster over another, as the panel requested. CDC advisers and agency officials are still working out whether to recommend that some people stick to their original vaccine if possible.

“A really important aspect of all of this is being clear and not dancing on the head of a pin so that we don’t confuse the American people,” said Beth Bell, a global health professor at the University of Washington.

The advisory panel’s recommendation was similar to Wednesday’s action by the Food and Drug Administration. The FDA did not take a position on whether people should stay with the original vaccine or switch to another one, saying it did not have the data to make such judgments.

The FDA has authorized a third shot of Moderna or Pfizer-BioNTech for anyone 65 and older, or any adults at high risk of severe illness because of underlying conditions, job exposure or because they are in institutional settings, and who have gone at least six months since their second dose.

It broadened eligibility much further for those who received the single-shot Johnson & Johnson vaccine to anyone 18 and older who has gone at least two months since getting the shot — criteria reflecting the lower protection afforded by that vaccine compared with the others.

Advisers to the CDC suggested in their all-day meeting Thursday that mixing and matching booster shots may appeal to consumers concerned about possible risks associated with their first vaccine.

“A lot of what our efforts are centered around is trying to mitigate risk as much as possible, both from disease as well as vaccination,” said Grace Lee, a professor of pediatrics at Stanford University School of Medicine and chair of the panel.

More data on the safety of booster shots for specific groups may help determine “whether or not a different boost would be appropriate, for example, for young women” who first received Johnson & Johnson, Lee added.

Some panel members questioned the wisdom of administering a second Johnson & Johnson shot to women of childbearing age, for instance, because of rare but serious risk of blood clots associated with that vaccine. Analyses of data for those who have received that shot suggest an increased risk of a rare type of clot, especially for women 18 to 49 years old.

About 105 million fully vaccinated people have received the two-shot Pfizer series, according to the CDC. About 70 million fully vaccinated people have received the Moderna shots. Only 15 million Americans were vaccinated with Johnson & Johnson shots, which arrived later and were delayed by an investigation of a rare adverse event, as well as a manufacturing problem. More than 11 million people have received a booster or an additional dose of a vaccine to date.

There still are restrictions on who qualifies and when for a booster. Starting six months past their last Pfizer or Moderna vaccination, people are urged to get a booster if they’re 65 or older, nursing home residents, or at least 50 and at increased risk of severe disease because of health problems. Boosters also were allowed, but not urged, for adults of any age at increased risk of infection because of health problems or their jobs or living conditions. That includes health care workers, teachers and people in jails or homeless shelters. Moderna’s booster will come at half the dose of the original two shots.

As for recipients of the single-shot J&J vaccine, a COVID-19 booster is recommended for everyone at least two months after their vaccination. That’s because the J&J vaccine hasn’t proved as protective as the two-dose Moderna or Pfizer options.

About two-thirds of Americans eligible for COVID-19 shots are fully vaccinated, and the government says getting first shots to the unvaccinated remain the priority. While health authorities hope boosters will shore up waning immunity against milder coronavirus infections, all the vaccines still offer strong protection against hospitalizations and death, even as the extra-contagious delta variant burned through the country.

Unvaccinated people are about six times more likely to test positive for COVID-19 and 11 times more likely to die from the illness compared to people who are vaccinated, though there are slight differences in risk based on vaccine type, according to newly released CDC data. 

The CDC published data Oct. 15 that breaks down the rate of COVID-19 cases and deaths by vaccination status and vaccine type. The rates are based on data from 16 public health departments — representing about 30 percent of the U.S. population — and cover April through the end of August. 

Five notes: 

1. Overall, unvaccinated people had the highest COVID-19 case and death rates. 

2. The COVID-19 case and death rates were slightly higher among Johnson & Johnson vaccine recipients, followed by Pfizer recipients and then Moderna.

3. As of Aug. 15, there were about 737 cases per 100,000 population among unvaccinated people — the highest rate during the period for which data was collected.

4. The case rates as of Aug. 15 for J&J recipients were about 172 cases per 100,000, followed by about 136 cases per 100,000 among Pfizer recipients, and 86 cases per 100,000 among Moderna recipients. 

5. The death rates as of Aug. 15 were nearly 13 per 100,000 among unvaccinated people, 3 per 100,000 for J&J recipients, about 1.4 per 100,000 for people who got Pfizer’s shot, and 0.69 per 100,000 for Moderna recipients.

Anthony Fauci, the chief medical advisor to President Joe Biden, said American drug regulator will consider whether those who have been inoculated with one dose of Johnson & Johnson (J&J) vaccine should be administered an mRNA-based vaccine, like Moderna or Pfizer as a booster shot to help induce a higher number of antibodies.

“If you boost people who have originally received J&J with either Moderna or Pfizer, the level of antibodies that you induce in them is much higher than if you boost them with the original J&J,” Fauci told reporters during a television interview.

Fauci’s comment comes after a second dose of the J&J vaccine was recommended by the Food and Drug Administration (FDA) for 18 years and above as a booster shot. FDA also recommended a third dose of the Modern vaccine as a booster shot to high-risk adults.

Both Pfizer-BioNTech SE and Moderna vaccines are based on mRNA technology while the J&J shot uses adenovirus like India’s Covishield. Experts opine that mix-and-match of vaccines if sanctioned will give individuals greater flexibility in deciding which booster shot they should opt for to help battle waning immunity against the virus.

The infectious disease expert had said towards the end of September that efficacy data on the pairing of vaccines will be available in the first two weeks of October, months after the National Institutes of Health started a mix-and-match trial of Pfizer, Moderna, and J&J shots on roughly 150 adults on June 1. All the participants were given a booster shot of a different vaccine three to four months after completing their first vaccine regimen.

Fauci also said individuals will have the freedom to choose which booster shot they would like to go for. “I believe there’s going to be a degree of flexibility of what a person who got the J&J originally can do, either with J&J or with the mix-and-match from other products,” he said.

More COVID-19 boosters are likely on the horizon: Last week, a U.S. Food and Drug Administration (FDA) advisory committee recommended a half-dose of Moderna’s vaccine for those over 65, as well as younger adults with certain health conditions and those who work in high-risk settings.

Subsequently, the committee unanimously voted to recommend boosters for Janssen/Johnson & Johnson recipients who are 18 or older, at least two months after their first dose. The FDA, which previously green-lit Pfizer boosters, is expected to follow both of the committee’s recommendations.

But when it comes to booster shots, one big question lingers: should people be mixing and matching by getting an extra dose of a vaccine other than the one they initially received?

A highly anticipated study of “mixing and matching” Covid-19 vaccines found the approach to be safe and effective, although the Moderna and Pfizer-BioNTech vaccines were found to spark stronger immune system responses than Johnson & Johnson’s vaccine. “Mixing and matching” refers to giving a booster dose of a vaccine different from the vaccine type that was used for the initial vaccination series.

According to the findings from the study by the National Institutes of Health, which was released last week, but has yet to be peer reviewed, participants who received a booster of a different vaccine than the one they originally got experienced antibody increases similar to or higher than those who received another dose of the same vaccine they were previously given.

The study found that people who received the Johnson & Johnson vaccine produced stronger antibody levels after they got booster shots made by Moderna or Pfizer, compared to boosters from Johnson & Johnson. Those who were originally vaccinated with the Pfizer or Moderna vaccines and received either company’s booster shot produced similarly strong immune responses, the researchers found.

Mixing and matching could help the booster rollout in the U.S., since people could receive whatever vaccine their pharmacy had on hand, rather than seeking out the shot they were originally given. As Alice writes, “The findings are encouraging because they suggest that it’s safe for providers to mix and match doses when it comes to boosters. … The ability to get any of the three vaccines will ensure that more people will get the additional shot.” However, at least for now, the FDA and CDC aren’t even considering whether to approve mixing and matching.

The World Health Organization (WHO) has said that it has recommended widespread use of the world’s first malaria vaccine called RTS,S/AS01 (RTS,S) for children in sub-Saharan Africa. According to the WHO, the vaccine is the result of 30 years of research and development by British pharmaceutical company GlaxoSmithKline (GSK) in partnership with the international non-profit organization Program for Appropriate Technology in Health (PATH) and with a network of research centers in Africa.

The WHO said on Wednesday its recommendation is based on results from more than 2.3 million doses of the vaccine that have been administered to more than 800,000 children in pilot countries Ghana, Kenya and Malawi since 2019, Xinhua news agency reported.

According to the WHO, more than two-thirds of children in the three countries who were not sleeping under a bednet were benefiting from the vaccine, bringing about a 30 percent drop in severe malaria, even when introduced in areas where insecticide-treated nets were widely used and there was good access to diagnosis and treatment.

The vaccine has a favorable safety profile, the WHO said, with no negative impact on the uptake of bednets, other childhood vaccinations, or health seeking behavior for febrile illness. “It’s safe, it significantly reduces life-threatening severe malaria, and we estimate it to be highly cost-effective,” WHO Director General Tedros Adhanom Ghebreyesus said at a press briefing.

According to the WHO, “the vaccine should be provided in a schedule of four doses in children from five months of age for the reduction of malaria disease and burden.” Malaria is a life-threatening disease caused by parasites that are transmitted to people through the bites of infected female Anopheles mosquitoes. It is preventable and curable.

The WHO’s records show that malaria remains a primary cause of childhood illness and death in sub-Saharan Africa. More than 260,000 African children under the age of five die from the disease annually. “This long-awaited malaria vaccine is a breakthrough for science, child health and malaria control,” said Tedros. “This vaccine is a gift to the world, but its value will be felt most in Africa, because that’s where the burden of malaria is greatest.” (IANS)

Newswise — Researchers at Johns Hopkins Medicine have found that a drug first developed to treat Alzheimer’s disease, schizophrenia and sickle cell disease reduces obesity and fatty liver in mice and improves their heart function — without changes in food intake or daily activity.

These findings, published online Oct. 7 in the Journal of Clinical Investigation, reveal that a chemical inhibitor of the enzyme PDE9 stimulates cells to burn more fat. This occurred in male mice and in female mice whose sex hormones were reduced by removing their ovaries, thus mimicking menopause. Postmenopausal women are well known to be at increased risk for obesity around their waist as well as at risk for cardiovascular and metabolic disease. Inhibiting PDE9 did not cause these changes in female mice that had their ovaries, so female sex hormone status was important in the study.

“Currently, there isn’t a pill that has been proven effective for treating severe obesity, yet such obesity is a global health problem that increases the risk of many other diseases,” says senior investigator David Kass, M.D., Abraham and Virginia Weiss Professor of Cardiology at the Johns Hopkins University School of Medicine. “What makes our findings exciting is that we found an oral medication that activates fat-burning in mice to reduce obesity and fat buildup in organs like the liver and heart that contribute to disease; this is new.”

This study follows work reported by the same laboratory in 2015 that first showed the PDE9 enzyme is present in the heart and contributes to heart disease triggered by high blood pressure. Blocking PDE9 increases the amount of a small molecule known as cyclic GMP, which in turn controls many aspects of cell function throughout the body. PDE9 is the enzyme cousin of another protein called PDE5, which also controls cyclic GMP and is blocked by drugs such as Viagra. Inhibitors of PDE9 are experimental, so there is no drug name yet.

Based on these results, the investigators suspected PDE9 inhibition might improve cardiometabolic syndrome (CMS), a constellation of common conditions including high blood pressure; high blood sugar, cholesterol and triglycerides; and excess body fat, particularly around the waist. CMS is considered a pandemic by medical experts and a major risk factor for heart disease, stroke, type 2 diabetes, cancers and COVID-19.

While PDE9 inhibitors remain experimental, they have been developed by several pharmaceutical companies and tested in humans for diseases such as Alzheimer’s and sickle cell. The current mouse study used a PDE9 inhibitor made by Pfizer Inc. (PF-04447943) that was first tested for Alzheimer’s disease, though eventually abandoned for this use. Between the two reported clinical trials, over 100 subjects received this drug, and it was found to be well tolerated with no serious adverse side effects. A different PDE9 inhibitor is now being tested for human heart failure.

To test the effects of a PDE9 inhibitor on obesity and cardiometabolic syndrome, the researchers put mice on a high-fat diet that led to doubling their body weight, high blood lipids and diabetes after four months. A group of female mice had their ovaries surgically removed, and most of the mice also had a pressure stress applied to the heart to better mimic cardiometabolic syndrome. The mice were then assigned to receive either the PDE9 inhibitor or a placebo by mouth over the next six to eight weeks.

In female mice without their ovaries (a model of postmenopause), the difference in median percent weight change between the drug and placebo groups was -27.5%, and in males it was -19.5%. Lean body mass was not altered in either group, nor was daily food consumption or physical activity. The PDE9 inhibitor lowered blood cholesterol and triglycerides, and reduced fat in the liver to levels found in mice fed a normal diet. The heart also improved with PDE9 inhibition, with ejection fraction (which measures the percentage of blood leaving the heart each time it contracts) relatively higher by 7%–15% and heart mass (hypertrophy) rising 70% less compared with the placebo. An increase in heart mass is evidence of abnormal heart stress. However, having this lowered by the inhibitor indicates stress on the heart was reduced.

The investigators found PDE9 inhibition produces these effects by activating a master regulator of fat metabolism known as PPARa. By stimulating PPARa, levels of genes for proteins that control fat uptake into cells and their use as fuel are broadly increased. When PPARa was blocked in cells or the whole animal, the effects from PDE9 inhibition on obesity and fat-burning were also lost. They found estrogen normally plays this role of PPARa on fat regulation in females, but when its levels fall like they do after menopause, PPARa becomes more important to regulate fat and so PDE9 inhibition has a greater effect.

“The finding that the experimental drug did not benefit female mice that had their ovaries shows that these sex hormones, particularly estrogen, had already achieved what inhibiting PDE9 does to stimulate fat-burning,” notes Sumita Mishra, the research associate who performed much of the work. “Menopause reduces sex hormone levels, and their control over fat metabolism then shifts to the protein regulated by PDE9, so the drug treatment is now effective.” According to the U.S. Centers for Disease Control and Prevention, more than 40% of people living in the U.S. are obese; and 43% of American women over the age of 60 — long past menopause — are considered obese. Kass notes that if his lab’s findings in mice apply to people, someone weighing 250 pounds could lose about 50 pounds with an oral PDE9 inhibitor without changing eating or exercise habits.

“I’m not suggesting to be a couch potato and take a pill, but I suspect that combined with diet and exercise, the effects from PDE9 inhibition may be even greater,” says Kass. The next step would be testing in humans to see if PDE9 inhibitors produce similar effects in men and postmenopausal women. “PDE9 inhibitors are already being studied in humans, so a clinical obesity study should not be that far away,” Kass says. The other researchers involved in the study include Nandhini Sadagopan, Brittany Dunkerly-Ering, Susana Rodriguez, Dylan Sarver, Sean Murphy, Hildur Knutsdottir, Vivek Jani, Deepthi Ashok, Christian Oeing, Brian O’Rourke and G. William Wong from Johns Hopkins Medicine; Ryan Ceddia and Sheila Collins from Vanderbilt University; and John Gangoiti and Dorothy Sears from the University of California San Diego.

The Johns Hopkins University has filed a patent on behalf of investigators Kass, Mishra and a prior member of the Kass laboratory, D.I. Lee, for the use of PDE9 inhibitors to treat cardiometabolic syndrome.