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Science Finally Figured Out How To Make Effective RSV Vaccines. Will Seniors Care?

The world has waited decades for vaccines to protect older adults against RSV. One, made by GSK, was approved by the Food and Drug Administration earlier this month. A second, made by Pfizer, is expected to follow by the end of May. Both will likely be in use this fall, in time to protect seniors going into the next RSV season.

So it's tempting to think the fight against respiratory syncytial virus in older adults is about to kick into high gear, that as early as next winter the United States might start to see a turning of the tide in terms of the number of seniors who develop severe disease from a bout of RSV.

Maybe. Hopefully.

But there are a number of hurdles standing in the way of making the most of the new vaccines. Those hurdles — from a lack of awareness about RSV to safety concerns to issues around who will administer these vaccines — are lower than those that could inhibit use of emerging new products designed to protect young infants from RSV. Still, there are hindrances ahead and they aren't insignificant.

For starters: There's a lack of appreciation of the impact RSV infections have on older adults, experts who research this virus acknowledge.

"Certainly those of us who study it feel like there is an enormous need," said Helen Chu, an associate professor of medicine at the University of Washington who specializes in adult infectious diseases. But Chu said there's a disconnect between how people in her field feel about the threat of RSV, and how it is regarded by the target audience and their doctors. "There is not such a perceived sense of urgency and need in the older adult population."

Ann Falsey, a professor of medicine at the University of Rochester, has spent decades mapping out the burden of RSV infection in this population. "RSV has a bit of an identity crisis," she told STAT.

The virus is one of the more than 200 pathogens that trigger what we think of as the common cold. For most of a person's life span, that's the way RSV infection manifests — as a bad cold. But infections in the very young and in older adults are more severe and can be dangerous.

The detailed research that Falsey conducted suggested that in terms of its impact on older adults, RSV is a close second to influenza. "In our outpatient group, RSV was twice as common, but flu more frequently led to doctors visits and hospitalizations in healthy people," she said.

The Centers for Disease Control and Prevention estimates that RSV infections in older adults in this country cause 6,000 to 10,000 deaths per year; 60,000 to 160,000 hospitalizations; and 900,000 to 1.4 million medical encounters. Others use higher figures.

"I think in places where we have looked systematically, it's clear that the burden of hospitalization and ICU admission for RSV in older adults is pretty significant," said Andrew Pavia, chief of the division of pediatric infectious diseases at the University of Utah. "[But] I think the average family doc and the average internist has very little appreciation of that."

That lack of recognition could make it difficult to get older adults to agree to be vaccinated against RSV.

It has been enormously challenging to get this age group to agree to take additional doses of Covid vaccine — even though Covid has killed nearly 855,000 Americans ages 65 and older. Only 43% of people in this demographic have received one of the updated bivalent boosters.

Flu shot uptake in this age group is better. Depending on which CDC measurement tool you look at, somewhere between 53% and 71% of people 65 and older get a flu shot annually. But it has taken years of promoting and cajoling from public health departments and family doctors to reach those levels.

Yet GSK, whose vaccine for older adults was the first RSV vaccine ever licensed, feels it may have a blockbuster on its hands. Luke Miels, GSK's chief commercial officer, told analysts in late April that demand for Arexvy, its RSV vaccine, could rival that of Shingrix, its highly successful shingles vaccine.

Pfizer also has a vaccine for this demographic barreling towards the market. (There are others further back in the pipeline as well.) Both vaccines will likely go before the CDC's vaccine advisory committee at its next meeting in late June. If the Advisory Committee on Immunization Practices recommends these vaccines — and CDC Director Rochelle Walensky signs off on the recommendations — both will be available this fall.

Both vaccines appear to prevent serious illness from RSV infection in older adults. In clinical trials, the GSK vaccine, Arexvy, had a vaccine efficacy of 82.5% in preventing RSV-related lower respiratory tract disease, and 87.5% efficacy in preventing lower respiratory tract illness that required medical attention. The Pfizer vaccine, which has the provisional name of Abrysvo, showed an efficacy of 66.7% at preventing RSV lower tract illness causing two or more symptoms, and 85.7% efficacy in preventing such illness involving three or more symptoms.

Airfinity, a health intelligence and analytics firm, estimates 29 million doses of the vaccines could be administered in the U.S. In 2023, and sales of the RSV vaccines for older adults could reach $3.3 billion by 2024, based on a per-dose price of $115. Neither company has indicated what it plans to charge, but cost-effectiveness modeling the companies provided the ACIP's RSV adult work group used $148 (GSK) and $200 (Pfizer) a dose as their price inputs.

Falsey, for one, thinks it will take time for demand for the vaccine to build. "I don't think in the fall it's going to have a huge uptake," she said. "Because it's not Covid, it's not perceived as the emergency that that was. But I wouldn't diminish it either."

The first-year uptake figure — 29 million — that Airfinity used in its analysis would require nearly 52% of Americans over the age of 65 to get an RSV shot this year — a tall order. If ACIP follows the FDA's lead and recommends the vaccines for people 60 and older, that projection would be an easier reach.

But here we hit hurdle No. 2: There's a fair chance ACIP will not recommend the vaccines for adults 60 through 64.

At its meeting in February, the work group — comprising ACIP members, CDC staff, and outside RSV experts — indicated it would not recommend all adults 60 to 64 get an RSV vaccine. The work group made clear it didn't think the vaccines would be cost-effective in that demographic. (See slides 72 and 75 in this presentation.)

Without a CDC recommendation, insurance companies would not be required to cover the cost of RSV shots for this age group. People who don't feel RSV is a big deal are unlikely to pay out of pocket for a shot.

Falsey doesn't think everyone over age 60 needs an RSV shot, but she worries an ACIP vote not to recommend the vaccines for people 60 to 64 could deter some people who would really benefit from getting one of the vaccines. "You're out running marathons and biking 20 miles, and you're not a smoker? You'll probably do just fine with RSV," she said in an interview. "But there's a lot of people in that age group that have underlying heart and lung disease. They have COPD. They have heart failure. And those people are at markedly elevated risk for having a bad outcome."

Another potential hurdle is a concern over safety. In clinical trials conducted to prove the GSK and Pfizer vaccines were safe and effective, three people out of the roughly 41,000 people who got one of the experimental vaccines developed Guillain-Barré syndrome or the related Miller Fisher syndrome.

GBS is a condition in which the immune system attacks nerves, leading to muscle weakness and in some cases paralysis. Most people recover, but some sustain permanent nerve damage. GBS can follow a viral or bacterial infection, like a stomach bug or a bout of influenza. But some vaccines, such as flu shots, have also been associated with a slightly elevated risk of developing GBS.

The background rate of GBS — the rate at which it occurs in the general population — is about 1 case per 100,000 people per year. Three cases in less than half that number — the people vaccinated in the adult RSV trials — gave pause to the members of ACIP's adult RSV work group, Drexel University College of Medicine pediatrics professor Sarah Long said at the February meeting.

Barney Graham, a professor of medicine and microbiology, biochemistry, and immunology at Morehouse School of Medicine, cautioned about jumping to conclusions about these vaccines and GBS.

"If you're enrolling compromised populations, older people, people with other complicating conditions, it's not that surprising that you would see things like this come up during a trial," said Graham, who with several colleagues solved the problem of how to make effective and safe RSV vaccines by stabilizing the F protein on the exterior of the virus' surface.

"How that is going to play out, you can't really study it until you get up to a million doses [of vaccine administered] or more," he said.

(Graham stands to earn modest royalties from sales of RSV vaccines and he has worked with a number of companies on them. Chu, Falsey, and Pavia have also consulted with several of the companies pursuing RSV vaccines and antibody treatments.)

It is too soon to say if the RSV vaccines will be among those that increase the risk of GBS, or if they are, by how much. It's also too soon to know whether an elevated risk of GBS would deter people from getting RSV shots.

GSK's Shingrix, the blockbuster shingles vaccine, has been linked to a slightly higher risk of developing GBS. An FDA-ordered label warning notes that about three extra cases of GBS are typically seen for every million doses of Shingrix that are administered. That doesn't appear to have dampened the appeal of the shingles vaccine; when it was first brought to market, higher-than-expected demand led to shortages. But people know about shingles and are motivated to avoid developing the painful condition.

These aren't the only problems that may be standing in the way of broad use of the adult RSV vaccines.

It's not yet clear if RSV vaccines will need to be given annually. But assuming they do — or even if they're needed every second year — they are likely to be given in the early fall, at or around the same time as flu shots and Covid boosters are offered. In an ideal world, you'd give all three shots at the same time because the easier it is for people to get vaccinated, the more likely it is they will do so. Requiring people to make and keep multiple appointments increases the risk they won't get all the recommended jabs.

But one can't assume vaccines can be given concomitantly without having a negative impact on vaccine efficacy. A Pfizer-funded study that Falsey led found that giving RSV and flu shots at the same time led to a lower immune response to the flu vaccine — though the effect was more pronounced in younger adults, who got regular-dose flu shots, than in older adults, who received high-dose flu shots. Other research has shown when RSV vaccine is given at the same time as a tetanus, diphtheria, and pertussis shot, the response to the pertussis component is dampened. More study is needed, but it may turn out that giving RSV vaccine with other shots is ill-advised.

There are also questions about who will administer these vaccines and how they will get compensated for having done so. The complexities around this could limit the number of places where people who want an RSV vaccine can get one. It will also definitely limit who can get an RSV jab for free under Medicare.

RSV vaccines will be covered under Medicare Part D, a program mainly designed to compensate for prescription drugs and other services rendered by pharmacists.

Flu and Covid shots are covered under Medicare Part B; doctors bill Medicare for the cost of vaccine doses they have purchased and for actually administering the vaccination. But there isn't a system in place that allows doctors to bill Medicare directly for vaccines covered under Part D.

There are some workarounds, said Juliette Cubanski, deputy director of the program on Medicare policy at KFF, formerly the Kaiser Family Foundation. Doctors can write a prescription for a vaccine and obtain it from a pharmacy. Using this approach, the pharmacy bills Medicare for the dose, and the doctor uses one of several online portals to seek compensation from the patient's insurance company for giving the vaccination. "It is possible for physicians to be able to implement Part D vaccines and be reimbursed, but it is difficult," Jason Goldman, an internal medical physician and the American College of Physicians' ACIP representative, said at the committee's February meeting.

Pharmacies could also administer RSV vaccines directly, though some states limit which vaccinations pharmacists can give and others require that pharmacists get a prescription from a doctor in order to vaccinate a patient.

"It is very complicated. And because it's complicated, there is, I think, legitimate concern that these complications and administrative barriers will represent access barriers to beneficiaries getting the vaccine," Cubanski said.

Adding to the complexity is the fact that Medicare Part D is a voluntary program. Older adults have to purchase Part D insurance — and not all do. Somewhere between 5 million and 6 million Medicare recipients do not have a Part D plan, Cubanski said. If those people want a vaccine that is covered by Part D, they have to pay the whole cost out of pocket.

"If the only way to get coverage for the RSV vaccine is through a Part D plan, and you don't have Part D coverage, you essentially are not covered," she said.

This article was updated to include data on how well the vaccines worked in clinical trials.

The Case For And Against The MMR Vaccine

by MICHAEL HANLON, Daily Mail

The MMR vaccine was introduced in October 1988 to provide a one-shot immunisation against three diseases - measles, mumps and rubella.

Since its widespread introduction, recommended by the World Health Organisation, rates of these diseases have fallen close to zero in immunised western populations.

FOR

Two doses of MMR gives 99 per cent protection against measles - the most serious of the diseases immunised against.

Most doctors believe giving the three vaccines at once is a good idea.

If given one at a time (three single vaccines followed by a booster for each), they have to be carefully spaced out.

The fear is that many parents would fail to complete the course. Children could also be vulnerable to infection between inoculations.

If more than 15 per cent of the population fail to vaccinate their children, measles epidemics could return to the UK.

Government-commissioned study (published in the Lancet in 1999) investigated claims that MMR was linked to autism and bowel disease. It concluded there was no link. Another study commissioned by the Department of Health and published in January this year also gave MMR the all-clear.

The scientific establishment remains convinced that MMR is the safest option. Professor Peter Lachman, President of the Academy of Medical Sciences, said: 'Even if there are dangers, all the evidence suggests that the chances of something nasty happening to you as a result of not getting vaccinated are around 100 times greater than something nasty happening to you if you do.'

AGAINST

Parents first voiced concerns over links between MMR and autism and the bowel condition Crohn's disease in the mid-1990s.

There were several cases of healthy children developing these conditions after being given the vaccine.

Increasing numbers of parents decided not to have their children vaccinated with the triple vaccine. They were supported by a handful of doctors happy to administer the vaccines in single doses.

Dr Andrew Wakefield, a consultant gastroenterologist, drew national attention to a possible link between the illnesses and the MMR method of vaccination in a study in 1998.

Dr Wakefield resigned from his post at the Royal Free and University College Medical School in North London earlier this month after being told his research did not 'fit in' with the college's strategy.

Dr Wakefield claims combining three live viruses in one injection could be dangerous.

He has speculated that the MMR vaccine damages the bowel, releasing toxins that travel to the brain and trigger autism.

He recommends children are vaccinated against mumps, measles and rubella one at a time.

Paul Shattock, of the Autism Research Unit in Sheffield, who is carrying out a large- scale study of 5,000 autistic children in Britain, supports Dr Wake-field's findings.

There is growing interest in his work in Canada and the U.S. Where similar concerns about MMR have been raised.

Statistics on autism seem to back up the suspicions of those opposed to the MMR vaccine.

Some research suggests a ten-fold rise in cases in the past ten years.

This corresponds to the introduction of MMR.

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The History Of MMR's Safety

by MELANIE PHILLIPS, Daily Mail

In the final part of today's investigation into the MMR vaccine, Melanie Phillips examines the history of the jab's safety in Britain.

Referring to the reviews by the MRC and the Institute of Medicine, as well as by the American Academy of Paediatrics and the Irish Department of Health and Children, the draft observed that these had unanimously concluded that a causal link between MMR and autism was 'neither proven nor disproven'.

The draft also agreed with the finding of these studies that, although the epidemiological evidence did not support the proposed link, it 'could not exclude the possibility that a very small number of children are affected differently from the large majority'.

It added that 'more extensive research would be necessary to provide the consistency and biological plausibility required to establish a causal link between viral infections and autism'.

In other words, in its early draft, the Medical Research Council concluded that the jury was still out on a link between MMR and autism, and more research was needed.

By the final, published version, this conclusion had vanished.

Many believe the only way to resolve this whole controversy is through fresh, undisputed clinical research.

'We don't think any more epidemiological studies have any purpose,' says Judith Barnard of the National Autism Society. 'They are a very blunt tool and do not pick up very rare occurrences.

'Scientists funded by the statutory agencies are firmly of the belief that Wakefield's studies are bad science, so we want to see more research by other people. And not, as the Medical Research Council is now doing, looking at more patient records, but more physiological studies.'

Since the Medical Research Council funds such studies, I asked its strategy manager, Dr Dukes, why this wasn't being done. 'We have not received any specific proposals to look at the effects of MMR,' he said. 'No scientists have approached us.'

But I have spoken to one highly regarded autism researcher who was one of a group that did offer the MRC precisely such a proposal, but which was unaccountably turned down flat. And this researcher says there have been others.

Now the Government has given the National Institute for Biological Standards and Control £300,000 to try to replicate Wakefield's research.

But the scientist who heads the institute, Dr Phil Minor, is being paid to advise GlaxoSmithKline, makers of the MMR vaccine, in the forthcoming lawsuit.

And one of his colleagues, Dr Mohammed Afzal, leader of the Institute's MMR programme, has been giving free legal advice to law firms representing the companies involved in the case.

This may be one reason why the Government has serious problems in regaining public confidence in the safety of MMR.

Parliamentary answers two years ago listed six members of the Joint Committee for Vaccination and Immunisation, and seven members of the Committee on the Safety of Medicines, who had declared financial or other interests in the drug companies involved.

According to parent David Thrower, more recent data issued by the Committee on the Safety of Medicines reveals that 19 members of these two committees now have such interests.

Perhaps the greatest cause for concern lies in the history of MMR in Britain.

In 1992, the particular type of MMR being used was withdrawn, as it was discovered that the Urabe strain of mumps vaccine in the mix was causing an alarming amount of aseptic meningitis, a disease that can kill infants.

The Department of Health then switched to an alternative MMR vaccine made by a different manufacturer.

But it had known of concerns about Urabe before it first introduced that vaccine in 1989.

Months previously, Canada had suspended its use of the Urabestrain MMR after discovering the risk of aseptic meningitis, and switched to an alternative vaccine. However, the Department of Health went ahead nevertheless and introduced it into the UK.

Dr Elizabeth Miller, head of the vaccines division of the Public Health Laboratory Service, was involved in eventually identifying the Urabe risk in Britain.

Although the Department of Health knew about the Canadian evidence before it introduced the Urabe vaccine here, she said, the risk was considered low, at one in every 100,000 doses. It was also unclear at the time, she said, whether the alternative vaccine posed a similar risk.

Nevertheless, she said, the department identified Urabestrain MMR as something for which surveillance needed to be introduced. So paediatricians had to complete a card every month saying whether there had been any adverse reactions.

This surveillance ran for two to three years. A few cases of aseptic meningitis were reported, but the apparent risk worked out at about one in 250,000 - even rarer than the reports from Canada.

However, among these cases, there appeared to be a cluster in Nottinghamshire where the risk was much higher. So Dr Miller conducted a study identifying every case of aseptic meningitis, regardless of whether they showed up in the surveillance reports.

'We linked this to the vaccine records and found many cases of aseptic meningitis linked to the vaccine that had not been picked up,' she said.

As a result, in 1992, Urabestrain MMR was suddenly withdrawn in the UK and replaced with the type of MMR vaccine used today. The revelation of this débacle poses some extremely urgent questions. Why did the department introduce Urabe- strain MMR, knowing there to be a question mark over its safety? Was this not tantamount to gambling with the health of Britain's children?

And what price the Government's vaccine safety surveillance when it failed, for two to three years, to detect the risk eventually picked up by Dr Miller?

How can we be sure there are no other adverse effects from the current vaccine, when doctors accept that the normal surveillance system fails to unearth most adverse reactions?

Above all, how can we trust the Department of Health's assurances that MMR is safe, when the original vaccine safety trials failed to spot the risk of aseptic meningitis from the Urabe- strain mumps component?

The Government says repeatedly that MMR is the safest way to protect our children. But why should we trust them when they got it so badly wrong before?

Tomorrow, I will look at the extraordinary way in which warnings about MMR have been brushed aside, and how Andrew Wakefield and his fellow researchers have refused to be silenced.

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