Eradicating meningococcal

NGP talks to Rino Rappuoli of Novartis about the breakthrough vaccines that could consign five deadly types of meningococcal disease to history.

“Treatment is always too late, so the only way to win with this disease is to prevent it.”
-Rino Rappuoli, Novartis

While meningococcal disease appears relatively rare in Western countries, with a frequency of around one person per 100,000 population, the disease does disproportionately affect certain populations, such as infants under nine months of age. The disease is more deadly in developing areas: in the 2009 epidemic season, for example, 14 African countries implementing enhanced surveillance reported a total of 78,416 suspected cases, including 4053 deaths.

Even in those countries where incidence of the disease is lower, it is still devastating, because it preys on the young and healthy, and its effects are so swift. A typical case could involve a young healthy teenager playing football in the afternoon, who comes home at 6 p.m. with a bit of a headache. By 10 p.m., the headache gets worse; he goes to the hospital and is put in intensive care. His condition continues to deteriorate, and within 48 hours, he could be dead.

Combine that with the fact that before the antibiotic era, the mortality of meningococcal disease was 80 percent, and the amount of fear inspired by the disease is understandable.

Although treatment has improved enormously in the last 100 years, as Rino Rappuoli, Global Head of Research for Novartis Vaccines and Diagnostics, points out, five to 10 percent of people who get meningococcal disease in Western countries still die.

“And between 20 and 25 percent of those who get the disease will have permanent sequelae,” he continues. “This means they will have to live for their entire lives with the consequences of the disease. It’s not uncommon for people to have arms or legs amputated; there are many cases where that has happened. The more modest cases of permanent sequelae will be hearing loss and learning difficulties. If you put the two things together, the number of people who either die or have permanent sequelae is pretty high.”

Global effects

According to the World Health Organization, meningococcal meningitis is a bacterial form of meningitis, a serious infection of the meninges, the system of membranes which surrounds the central nervous system. It can cause severe brain damage and is fatal in 50 percent of cases if untreated.

Several different bacteria can cause meningitis; of these, Neisseria meningitidis has the potential to cause large epidemics. Twelve serogroups of N. meningitidis have been identified, five of which (A, B, C, W135, and X) can cause epidemics. Geographic distribution and epidemic capabilities differ according to the serogroup.

As Rappuoli explains, from a disease standpoint, there’s no difference between the groups. “From an epidemiological point of view, the reason they’re different is because these bacteria all have a capsule of polysaccharides. That means they are surrounded by a kind of gelatin made by sugar. The chemical composition of this sugar changes, and, therefore, depending on the chemical composition, they are recognized by different antibodies.

“In different geographical areas, you can have several groups. Although, regardless of that geography, whatever picture you have is a snapshot of today. In the same geographical area, things change over time, so these bacteria have changed in different areas over different times.

“Today, globally, meningococcal B is a major cause of disease in the developed world. But in Africa, the most potent is A, and A is not present in Europe and the US, it is only present in Africa, Asia and Russia. In Europe, it is mostly B, although there are others coming up, including Y and W.”

“In the US, it’s more or less equal 30/30/30 for B, C, and Y. But, for instance, 15 years ago, in the US it was almost exclusively B and C. Y came out over the last 10 years. So you cannot say the US has only Y and B, because it changes.”

Prevention

One of the obstacles to successful treatment of meningococcal meningitis is the speed at which it strikes. As Rappuoli says, “By the time you recognize it, it’s too late.” This being the case, the only way to win against the disease is to prevent it, which is why Rappuoli is so excited about Menveo, which was approved earlier this year by the FDA for administration in the US  for people aged between 11 and 55, and was granted a marketing authorization by the European Commission for all 27 member states in March for use in people 11 years of age and older. It is the first conjugate vaccine commercially available in Europe that helps protect against four major groups of meningococcal disease: A, C, W135 and Y.

The vaccine has also been tested extensively on lower age groups, including infants starting from two months of age. Rappuoli calls the data “beautiful” and says the company plans to submit license applications for all ages down to two months.

The launch of Menveo is even more of an achievement when you consider that researchers have been working on the development of vaccines for meningococcus for more than 20 years. The first conjugate vaccine developed was in the 1990s for meningococcus C, which had a high incidence in the UK at the time.

Rappuoli tells the story: “Between 1999 and 2000, public health in the UK licensed vaccines for meningococcus C from several companies, and together we vaccinated the entire country. From one month of age to 18 years of age, one year, an entire country. And the result was that in one year, the disease practically disappeared. Previously, every year in the UK they used to have 1500 cases per year, resulting in more or less 150 dead and 300 permanent sequelaes. Now that’s largely gone.”

“In 10 years we prevented 15,000 cases and 1500 deaths. That’s why I’m so confident that Menveo will work, because one component has already done its job. Because of these very good results with meningococcus C, we decided to use the same technology to do Menveo, which works against four of the five types.”

After the success of the meningococcus C vaccine, Rappuoli was determined to find a vaccine that would cover the five main serogroups: A, B, C, W135 and Y. Menveo represents the culmination of 10 years of successful work on a conjugate vaccine for A, C, W135 and Y, using the same technology that was used to develop the C-only vaccine in the 1990s. But as Rappuoli explains, this technology could not be used for B. “The reason is pretty simple: B also has a gelatin that surrounds the bacteria, like the others. But unfortunately the chemical composition of this sugar is identical to a sugar that we have in our bodies.”

“Our immune system does not recognize this is a foreign piece of bacteria, but as our internal material, so it’s not able to provoke a response. Because of this, the Menveo technology could not be applied to B. And since this very successful technology could not be applied, many people tried in the 1990s to solve the problem of B, and it was one failure after the other.”

“I also tried in the mid-1990s, and I reached the conclusion that with the technologies we had at that time, making a vaccine for B was impossible. So I shut down the project in my lab because I felt it was useless to work on something where there was no hope because the technology was not there.”

Rappuoli did not forget the idea, however, and was always looking for new technologies that might help solve the problem. In 1995, when Craig Venter of Celera Genomics published the sequence of the first bacterial genome, its potential for the development of a meningococcus B vaccine came to Rappuoli’s mind immediately.

“That was a new power for technology, with information that nobody had seen before,” he recalls. “I jumped on the idea that maybe this could help us to solve the problem. I went to talk to Craig Venter, and asked him whether he would sequence the genome of meningococcus B, so we could use that information on the genome to try to come up with new solutions.

“He agreed to sequence the genome, and in the first few months of collaboration I immediately felt that we had a new revolutionary technology and we were going to find a solution. Just to give you an idea of the situation we found ourselves in when we started, with the old technology, the people who had been working on meningococcus for a century had found maybe 10, certainly no more than 15 possible antigens for a vaccine. Now we could predict at least 600. It was very exciting because it was like we discovered a new world that we never new existed.

“And among the 600, eventually, we found antigens that could solve the meningococcus B problem. After a lot of work, we are at the end of phase III in infants in the European trial. Ten years later, we are positioned where we believe we have a vaccine.” Novartis plans to submit a file for their meningococcus B vaccine with EU regulatory authorities by the end of 2010.

Adjuvant needed

In addition to his work on meningococcus, Rappuoli has also been carrying out extensive research in the influenza space. He explains that while the existing influenza vaccine is very good if given to healthy adults, in the elderly and those with weaker immune systems, it works less well. Rappuoli and his team began working on a new vaccine that would respond better in those whose immune systems were less robust.

“We did a number of trials and finally in 1997, we licensed our first adjuvant, and then in 2000, it was licensed all across Europe and then in 50 different countries worldwide,” Rappuoli says. “To give you an idea of the importance of this, in the previous century from 1900 to 2000, only one other adjuvant was licensed, in 1924. So our licensing a new adjuvant for human use was something that happened once in a century. We licensed it to improve the efficacy of the vaccine, which we did, and it worked.

“Then in 1997, when the first H5N1 avian influenza strain came along, we were the first ones who were able to make a vaccine out of that strain. It was difficult to make, but we made it and tested it in people, in phase I. And we decided to test it with or without an adjuvant.

“To our great surprise, we found that the H5N1 vaccine without the adjuvant did not work at all in humans. At that time, H5N1 had disappeared, and no one noticed. But then in 2004-2005, when H5N1 came back and started to travel worldwide, the vaccine was needed immediately. They made the conventional vaccine, and found it didn’t work.

“Eventually, everybody agreed that for H5N1 you need an adjuvant. There’s no way you can get a good vaccine without it. Now everybody has developed emulsions that are very similar to ours. Also, all this preparation we had made for H5N1 was very useful when H1N1 surfaced.”

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Biography

Rino Rappuoli is Global Head of Research for Novartis Vaccines and Diagnostics.

 

 

 

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Epidemic in the southern hemisphere

Rino Rappuoli was able to use his expertise to advise the New Zealand government, which had been suffering from a decade-long epidemic of serogroup B meningitis during the 1990s.

Unlike its counterparts in the UK and the US, the New Zealand epidemic was caused by a single bacterial strain. Despite the fact that this single strain could be overcome using currently available technology, the country was struggling to come up with a vaccine. In 2000, Rappuoli gave a talk in Sydney about the first result using the genome sequencing technology, which had just been published in Science.

“In my presentation I said we would probably solve the problem of meningococcus B,” Rappuoli says. “Someone  came to me and said, ‘I’m from New Zealand and I hope you’re right, because we have a big problem there.’

“And I said, ‘I hope you don’t have to wait for my new approach because you have an epidemic and children are dying every day, and my new vaccine is going to take 10 years. You have an epidemic caused only by one strain: you don’t need this sophisticated approach, you can use conventional technology.’”

“He asked me if I thought the epidemic could be ended right then, and I said yes. I told him the reason they did not have a vaccine was not because it was not technically possible, but because it was a problem that existed only in New Zealand. 

“I told him that his government had to convince vaccine manufacturers to develop a vaccine only for New Zealand. We had some conversations and they came to spend a few days with me, and we made a plan. Six months later, the New Zealand government decided to develop the vaccine. By 2004, the vaccine had been developed and phase I and phase II had started. Then we could start vaccinating using the same approach that we had used in the UK. We vaccinated every single person from two months upwards, and by 2005, the epidemic had disappeared.”

Menveo

Menveo was developed using conjugate technology, which was pioneered by Novartis Vaccines in the development of its meningococcal group C conjugate vaccine, Menjugate. A conjugate vaccine is developed by attaching a polysaccharide antigen – the key component of a vaccine that prompts the body to respond to infection – to a carrier protein in order to enhance the body’s immune response to the vaccine.

When utilized in a national immunization program, conjugate vaccines (such as those designed to help protect against Hib, pneumococcal and meningococcal group C disease) have reduced the number of people (both vaccinated and unvaccinated) who carry the bacteria that cause the disease. Novartis is currently studying the long-term safety and immunogenicity of Menveo, and is considering clinical studies on carriage. 

Menveo has been administered to more than 18,500 people and is currently in multiple Phase III clinical studies in infants and toddlers worldwide. The FDA recently approved Menveo for use in 11-55 year olds, and the European Commission approved Menveo for use in adolescents and adults from 11 years of age.

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Meningococcal meningitis key facts

Meningococcal meningitis is a bacterial form of meningitis, a serious infection of the thin lining that surrounds the brain and spinal cord.

The meningitis belt of sub-Saharan Africa, stretching from Senegal in the west to Ethiopia in the east, has the highest rates of the disease.

In the 2009 epidemic season, 14 African countries implementing enhanced surveillance reported a total of 78,416 suspected cases, including 4053 deaths, the largest number since the 1996 epidemic.

Meningococcal polysaccharide vaccines are available to control the disease.

A new meningoccocal conjugate A vaccine developed specifically for Africa should be available by the end of 2010.

Source: World Health Organization

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Progress of the meningococcol disease

 

Transmission of meningococcal

Meningococcal meningitis bacteria are transmitted from person to person through droplets of respiratory or throat secretions. Close and prolonged contact – such as kissing, sneezing or coughing on someone, or living in close quarters (such as a dormitory, sharing eating or drinking utensils) with an infected person – facilitates the spread of the disease. The average incubation period is four days, but can range between two and 10 days.

Symptoms of meningococcal

The most common symptoms are a stiff neck, high fever, sensitivity to light, confusion, headaches and vomiting. Even when the disease is diagnosed early and adequate treatment is started, five percent to 10 percent of patients die, typically within 24 to 48 hours after the onset of symptoms.

Diagnosis of meningococcal

Initial diagnosis of meningococcal meningitis can be made by clinical examination followed by a lumbar puncture showing a purulent spinal fluid. The bacteria can sometimes be seen in microscopic examinations of the spinal fluid. The diagnosis is supported or confirmed by growing the bacteria from specimens of spinal fluid or blood, by agglutination tests or by polymerase chain reaction (PCR). The identification of the serogroups and susceptibility testing to antibiotics are important to define control measures.

Treatment of meningococcal

Meningoccocal disease is potentially fatal and should always be viewed as a medical emergency. Appropriate antibiotic treatment must be started as soon as possible, ideally after the lumbar puncture has been carried out if such a puncture can be performed immediately. If treatment is started prior to the lumbar puncture it may be difficult to grow the bacteria from the spinal fluid and confirm the diagnosis.

Source: World Health Organization