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AWith the threat of Lyme disease growing and fears surrounding it spreading faster than ticks carrying the infection, researchers are developing two vaccination or vaccine-like approaches to prevent this disease from spreading. more and more problematic. But do not expect to have one soon. According to their developers, they are at least in three to five years of clinical use.
It may seem long to wait, especially since there are several vaccines against Lyme disease for dogs. But it took researchers nearly two decades to get close to that – for the second time. The developers have had to face a tough battle since LYMErix, a short-lived vaccine, was pulled off the market in 2002 due to insufficient demand and lawsuits for potential adverse effects, not to mention increasing mistrust with regard to vaccines.
"The failure of LYMErix has greatly cooled," said Sam Telford, a professor of vector and public health infections at Tufts University, who participated in conducting the trial. Clinic LYMErix. "The companies said," Look, we just do not want to go. "There was a lot of negativity around creating a new vaccine against Lyme disease."
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As work progresses on these two new approaches, the question for many of them is: is the market ready for a new Lyme disease vaccine?
A closer look at new products
One of the newer approaches is a vaccine that stimulates the immune system to make antibodies that can attack Borrelia burgdorferi and other types of Borrelia, the bacteria that causes Lyme disease. The other is an injection of a single antibody.
Both use an approach similar to that of LYMErix. Here is an overview of the process:
When an infected tick bites someone and starts feeding on its blood, the bacteria that causes Lyme disease can slowly move from the intestine to the tick's salivary glands, then transfer from bite to bite. But if the person's blood contains antibodies against the bacteria, it can kill Borrelia in the tick's gut before the bacteria can move to the salivary glands, preventing transmission to humans.
The vaccine, called VLA15, is being developed by Valneva, a biotechnology company based in France.
It targets the six most common types of Borrelia, said Thomas Lingelbach, President and CEO of Valneva. This means that it would work as well in North America as in Europe, where Lyme disease is a growing threat.
In addition to the adult VLA15 test, Valneva plans to try children aged 5 and under and possibly children under 5 years of age. This would expand the market for parents wanting to vaccinate their children. This is an advantage over LYMErix, which was limited to 15 to 70 years old.
Although some measures can be taken to prevent Lyme disease, including wearing protective clothing, using an insect repellent and looking for ticks after going on the outside, a number of These techniques are difficult to consistently apply, especially in children, said Dr. Lise Nigrovic, a pediatric emergency physician at the Boston Children's Hospital that studies Lyme disease. She recently published a study showing that only 1 in 5 children with Lyme disease remembers having a tick bite.
"Lyme disease is causing a lot of concern, as some parents are telling kids not to play outside or limit hours of play," Nigrovic said. "They behave differently because of this worry. Vaccines are therefore attractive.
The Food and Drug Administration designated VLA15 as an expedited procedure in July 2017. Valneva completed the initial safety studies in a Phase 2 clinical trial. According to a press release, VLA15 " did not have any associated safety issues ". determine the dose. According to current estimates, Lingelbach said that Valneva plans to test the vaccine in the context of a clinical trial of at least 15,000 people. This vaccine should be available in four or five years.
The approval process of the FDA is long. But Telford said it might be easier for VLA15 than for LYMErix, given the number of people who know about Lyme disease today and likely to participate in clinical trials.
"Finding people is going to be a child's game compared to what it was in the 1990s," he said. "I do not see why they could not benefit people from here until 2024."
A different approach, developed by the University of Massachusetts Medical School, is called Lyme Pre-Exposure Prophylaxis (Lyme PrEP). Unlike a vaccine, Lyme PrEP provides a single defensive antibody, said Dr. Mark Klempner, executive vice chancellor of MassBiologics and professor of medicine at the university, who leads the product development efforts.
According to Klempner, this approach could reduce the risk of side effects. This would also make the recipient immune to Lyme disease from the day he would receive the injection, instead of waiting a few weeks for his immunity to develop, as most vaccines predict – or even longer for multiple dose vaccines, as was the case for LYMErix.
Some critics are worried that, since these new approaches only protect against Lyme disease, recipients may be less attentive to preventing tick bites and thus expose themselves to other diseases. related to ticks, such as babesiosis. But Klempner said that specificity is necessary.
"When you try to hit several birds with a rock, you run the risk of having a lot more out-of-target effects," he said. "Our approach is to start with the most important, Lyme disease. I think everyone agrees that it is the biggest public health problem related to tick-borne diseases. "
Klempner's team hopes to open a Phase 1 clinical trial on Lyme PrEP in 2020. He added that the product could be available by 2022.
The rise and fall of LYMErix
Part of the industry's reluctance to develop a new vaccine dates back to the 1990s, when two pharmaceutical companies, SmithKline Beecham (now GlaxoSmithKline) and Pasteur Mérieux Connaught (now Sanofi (SNY) Pasteur) went head-to-head to develop the Lyme disease. vaccines. A few days before Christmas 1998, LYMErix won the race and received approval from the FDA.
The launch of a new vaccine on the market would be an unfavorable time.
In the beginning, the vaccine worked well: 1.4 million doses were distributed in July 2000. One of the first problems was that LYMErix required three injections in 12 months and that the duration of the immunity was not clear. . Another is that it has not been approved for people under 15 years old. Some people felt that it should have been more effective because it worked for about 80% of people who were vaccinated.
Safety issues started to appear soon after people started taking LYMErix. Some recipients began reporting joint pain and other effects that they attributed to the vaccine. One year after the vaccine was approved, a class action suit was filed against SmithKline Beecham on behalf of 121 people. Although the lawsuit was finally settled – it did not provide any compensation to the plaintiffs – the publicity about it reduced the interest in the vaccine.
At the same time, growing mistrust of vaccines may have aggravated LYMErix's difficulties.
When a report published in 1998 in the Lancet identified an alleged link between the common MMR vaccine and autism, the study – retracted and considered fraudulent – sparked a renewed concern about the safety of vaccines. In October 1999, a new vaccine against rotavirus, the leading cause of diarrhea in infants and young children, was withdrawn from the market because its use was linked to a higher than expected risk of potential bowel obstruction. mortal called intussusception.
An advisory committee convened in 2001 by the FDA found no evidence that LYMErix has caused human arthritis or an unexpected number of adverse events. But the growing suspicion of vaccines in general and the publicity about possible side effects had already weighed on the assimilation of LYMErix. SmithKline Beecham planned to sell only 10,000 doses in 2002.
The company withdrew LYMErix in February 2002, citing poor market results.
"This is a fiasco for no other vaccine," said Dr. Stanley Plotkin, Emeritus Professor of Pediatrics at the University of Pennsylvania and a senior researcher in the field of vaccines. "The activity on the ground has been brought under control because companies are worried that the same thing that happened to GSK will happen to them."
Pastor Mérieux Connaught has never applied for a license for her vaccine, so called ImuLyme, despite tests and promising clinical trials.
In April 2013, Baxter International (BAX) released promising data on a Lyme vaccine under development. But Baxter quickly sold its vaccine portfolio. He ended up with Shire, who decided not to continue the vaccine.
At some point after the disappearance of LYMErix, Telford acknowledged that it would be cheaper to reactivate a vaccine than he deemed safe and effective and began trying to bring it back to life. But, he said, GlaxoSmithKline (GSK) would not have the right to sell the product if the company could be held responsible for future problems.
"I am very discouraged after 34 years working on Lyme disease," said Telford. "In fact, I'm so frustrated that maybe I could publish the recipe on YouTube and tell it to make it yourself."
The possible side effects and a hesitant climate with regard to vaccines did not, however, completely slow down the canine vaccine market. Since the first Lyme disease vaccine for dogs was available in the early 1990s, several others have been developed and millions of dogs have been vaccinated.
The road ahead
In a way, the market for Lyme vaccine is very promising today compared to two decades ago. On the one hand, the number of people affected by the infection has increased significantly over the past 20 years.
In 1998, the year of LYMErix approval, 16,802 cases of Lyme disease were confirmed in the United States. Today, about 30,000 confirmed cases are reported each year, but the CDC estimates that the actual number is closer to 300,000 per year and that it has steadily increased over the last 25 years. In Europe, the number of cases reported in 2010 was more than seven times higher than in 1990.
The extent of the infection has also increased. Since the first group of confirmed cases was reported in Old Lyme, Connecticut, in 1977, ticks are now found at the origin of Lyme disease in 44 states. A 2016 study found that ticks that spread Lyme disease were present in 44% more counties than in 1996. Coastal states and north-central states still record the highest number of cases, Pennsylvania tops the list with more than 9,000 confirmed cases in 2017.
"It's a common disease and it's ridiculous not to try to prevent it," said Plotkin.
As more and more people contract Lyme disease, the economic burden to diagnose and treat it has also increased. A 2015 study found that Lyme disease could cost the US health care system up to $ 1.3 billion a year.
"There is a hunger in the market for something to prevent infection," Nigrovic said.
However, developers will face some challenges, especially those that persist after the withdrawal of LYMErix.
On the one hand, public attitudes towards vaccines may be even less attractive than they were in 1998.
"There is still this anti-vaccine thread that is independent of Lyme disease," Nigrovic said. "It will be something that comes into play."
Any vaccine against Lyme disease would probably be optional, which could reduce the opposition of groups reluctant to the vaccine. But there is another possible point of contention: VLA15 and Lyme PrEP are both targeting the same Borrelia protein as LYMErix – the outer surface protein A (OspA).
The approach used to target OspA in LYMErix was related to concerns about potential side effects. Although studies have not confirmed the link, VLA15 uses a slightly modified vaccine approach and Lyme Pryme directly provides a single antibody, both of which can bypass the suspected problem. But Telford said some people may still oppose a vaccine that targets OspA.
"I think Valneva will have a problem with the activists," he said, noting that he had spoken informally with some community groups. "The general statement was:" No OspA vaccine, no how. "
Dr. Phillip Baker, executive director of the American Lyme Disease Foundation, a non-profit organization run by volunteers, has agreed. "They are already criticizing the vaccine and it has not even been published," he said. "There is so much misunderstanding about Lyme disease. There is an element of suspicion. "
However, Roberta Clarke, a health care marketing expert and associate professor at Boston University, has been affected by Lyme disease three times. She said some members of the Lyme activism community might support a new preventive approach, especially people who are frustrated with current treatments, which usually consist of antibiotics.
According to Telford, some activists are also asking for more research funding for tick-related diseases.
"We all know there is a problem here. People are fed up, "he said. "There are people who are angry enough to force their lawmakers to do something about it."
And it may work. In 2016, the Congress set up the Task Force on Tick-borne Diseases, which presented its first report in 2018. The National Institutes of Health also launched a call for proposals for the prevention of tick-related diseases. with $ 6 million to fund projects in 2020.
Lorraine Johnson, general manager of LymeDisease.org, a nonprofit advocacy group, said developers of new approaches may avoid a problem she observed with LYMErix: a lack of communication between the manufacturer and the community. "You really want manufacturers to reach out to the Lyme community and work with them in a much more collaborative way, coming up and with full disclosure," she said.
Lingelbach said Valneva was engaging with thought leaders and patient advocacy groups, but it was difficult given the company's current distance to licensing its vaccine.
Johnson also said that it was too early to say how activists and community members would react to VLA15.
"The Lyme community is not an anti-vaccine," she said. "It's just a question of whether it's the right vaccine at the right time and whether [developers] engage with the community as collaborative partners. "
Companies will also have to hire doctors this time, Plotkin said. LYMErix has been sold directly to consumers, but Mr Plotkin said that Valneva should involve doctors to make sure they are aware and that they feel comfortable to recommend the vaccine.
In addition to "a very nuanced roll-out of public health," Nigrovic said reliable data on safety and efficiency could override past mistrust.
Klempner was optimistic. "We have learned some very important lessons from the LYMErix debacle, which some people might categorize," he said. "It certainly remains the only safe and effective vaccine withdrawn from the market."
During LYMErix's brief stint on the market, Clarke was among the recipients. Having had Lyme disease twice, she decided to try the vaccine. Even after receiving the last shot of LYMErix, Clarke said she contracted Lyme for the third time.
Despite this, Clarke said she would still try a new vaccine.
"If the research is strong enough to show that it is effective and side effects are minimal, of course," Clarke said. "Of course."
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