EXCLUSIVE: Interview with the CDC on the Approval of New Meningitis Vaccine

Last year, almost all of the Princeton students received two doses of the meningitis B vaccine called Bexsero, which was developed by Novartis. Bexsero, while not formally approved by the FDA in the US, had been approved in other nations globally and as a result, was recommended by the CDC and FDA for use to control the Princeton outbreak. Data was also collected by Princeton and CDC on the effect of the vaccine on the Princeton outbreak.

However, recently, the FDA approved Trumenba, developed by Pfizer, as a vaccine for meningitis B. At the same time, Bexsero, used at Princeton, has still not been approved by the FDA. Why has the vaccine which was used not only at Princeton but also as UCSB not approved by the FDA? Does data suggest that Trumenba performs better than Bexsero? Or are there other reasons behind approving Trumenba?

Below is a Q&A with Dr. Manisha Patel, who has been involved been involved with the Princeton meningitis outbreak. The discussion focuses on the differences between the two vaccines, reasons why Bexsero was recommended for the Princeton outbreak and reasons why Trumenba was approved first by the FDA.

PPHR: What makes meningitis B so difficult to vaccinate against? I understand that in morbidity and mode of transmission, all serogroups of meningitis are relatively similar.

PATEL: The main question is “Why don’t we have a meningitis B vaccine when vaccines for serogroups A, C, W and Y are available?” The major reason that developing a meningitis B vaccine is so challenging is that the polysaccharide capsule, the blanket that covers meningococcal bacteria, is the main target in the other vaccines. The problem is that the meningitis B polysaccharide capsule is closely similar to human neuronal cells, causing, first of all, a poor immune response, and second of all, a potential autoimmune response. As a result, vaccine development has focused on subcapsular proteins, but the problem with those proteins is that they are very diverse among various meningitis B strains. Meningitis B is the serogroup, within that the various strains are genetically distinct, making the strain at Princeton distinct from the strain at UCSB. Because they’re so diverse it’s hard to make a vaccine that will cover all the circulating strains in the US. When the FDA moves forward with whether or not to license a vaccine, it has to make sure it was immunogenic, and we also have to make sure it would cover all the circulating strains in the US.

Both vaccines used data from the outbreaks at Princeton and UCSB and are effective against both strains. Because of the outbreaks, both vaccines got priority review designations, meaning that they have expedited licensure. Actually, the action date for Trumenba was February 14^th, 2015, but the FDA worked really hard these last two days to accelerate that. The action date for Bexsero is March 24, 2015. But again, this is an end date. By that date, an announcement regarding licensure is expected for Bexsero, but it is possible that it will occur sooner.

PPHR: Do you know why Bexsero was recommended to interrupt the outbreaks at Princeton and UCSB instead of Trumenba?

PATEL: Well, Trumenba wasn’t licensed anywhere, and we felt that Bexsero, which was licensed and starting to be used and recommended by agencies elsewhere, would be more appropriate. Bexsero also requires only two doses [as opposed to Trumenba, which requires three], so we felt that from a logistics perspective, it might simply be easier. But the main reason was that it was licensed elsewhere and would be more appropriate to bring into the Princeton and UCSB outbreaks. 

PPHR: Can you speculate as to why Trumenba was approved first, especially when Bexsero is more available in other countries and favored when choosing a vaccine for Princeton and UCSB?

PATEL: It’s really simply a regulatory process in which Pfizer (Trumenba) and Novartis (Bexsero) must submit an application, and Novartis submitted this later than Pfizer. It actually has nothing to do with whether there is anything concerning in the data, but rather that each of them have independent applications which were submitted separately at different times. I would talk to the FDA for specifics regarding this process for Trumenba and Bexsero, but it is primarily what determines the action date, or deadline, for licensure.

PPHR: What are the differences between Trumenba and Bexsero? How do they induce immunities against meningitis B differently?

PATEL: The big difference is that they have different antigens, [the serogroup-specific subcapsular proteins that the vaccine attacks]. The second thing is that Trumenba requires three doses whereas Bexsero requires only two. These are the two main differences. Both of them target the subcapsular proteins. This is what makes meningitis B so challenging to fight in the U.S., because there are so many diverse strains of serogroup B. In previous outbreaks, such as the one in Brazil, a vaccine would only be helpful for that specific genetic strain [and would be used to interrupt the outbreak]. In contrast, Bexsero and Trumenba are effective against most strains of meningitis B.

PPHR: How do you expect the CDC to recommend this vaccine be used?

PATEL: That is definitely the next step for the CDC—now that it has been approved, what is the best use of this vaccine and the most appropriate setting? All of these things are being considered—firstly outbreaks and how to use the vaccines in high-risk people. High-risk individuals are those with comparable immune deficiencies, functional or anatomic asplenia, who work in a laboratory with high volumes of bacteria, or, like at Princeton and UCSB, those in a community experiencing an outbreak.

Our goal is to make these recommendations first. Then, we consider how to use it in more expanded groups, and that’s the data that we will be continuing to review. Right now that’s all the data that we have to review – we do not have data on how long these vaccines last – and the main reason we do not know is because it went through an expedited review program. Usually, if it’s through traditional licensure, you would have all this data available because traditional licensure takes so long. It is not that the FDA approved Trumenba on partial data, but that the criteria that you need for licensure is different from the data needed to give informed recommendations. We have two-year data for Bexsero; we have no duration data yet for Trumenba. This is part of the data we need to review in order to make recommendations as to how to best recommend these vaccines.

We will, of course, be recommending the use of the vaccine in outbreak control. Beyond these, the advisory committee, which meets three times a year and is composed of experts in many fields across countries, will interpret the evidence and decide what the recommendations are for expanded groups. Now that it is approved, anybody can ask for this vaccine just like anybody can ask for a vaccine against typhoid fever or Japanese encephalitis—there are plenty of vaccines out there—but recommendations give doctors an idea of exactly what they should do if a 16-year-old comes in and asks for the appropriate vaccines. 

PPHR: Do you expect that this vaccine will be recommended to be required by college campuses, considering the higher rates of infection of meningococcal disease on college campuses?

PATEL: Yes. In fact, the chair of ACIP is on the meningococcal workgroup. We get feedback from everybody on this topic. We were very happily surprised to have a vaccine approved. It’s a huge step forward in controlling meningococcal disease. In terms of what colleges can do, I can’t speak to that, but we’re thinking about all of these different types of recommendations.

PPHR: Why were Trumenba and Bexsero given the accelerated approval process?

PATEL: Because of the outbreaks. Expedited programs are specifically meant for serious or life-threatening conditions in which there is no other adequate approved alternative. At the time of the outbreaks we had no other means of controlling it. So at the time of the outbreaks, we were communicating with the FDA: can we use this vaccine [Bexsero], it’s already approved in Europe? And, we all agreed it was the right thing to do. The circumstances were serious and life-threatening, which is why both of these vaccines were granted accelerated approval.

PPHR: What is the biggest challenge in controlling an outbreak? I know that meningitis, once contracted, acts very quickly.

PATEL: Before the vaccine became available, the biggest challenge was raising awareness, such as hygiene and reducing the risk of transmission. Now that we have a vaccine available for outbreak response, I think the hardest thing is knowing whether it will be an outbreak or whether there will be additional cases. In most cases, there are a cluster of cases, close together, and then it goes away. At Princeton, that’s not what happened. There was a case every few weeks, every month, then it jumped over the summer. It’s extremely hard to predict whether you will have additional cases. The second thing is that it is really scary. It’s scary for parents, for students, and schools are responsible for doing the right thing, because the answer is not always to vaccinate right away, because of the specific guidelines that define an outbreak [beyond three cases in a period of time]. The outbreaks at Princeton and UCSB actually redefined what an outbreak is in terms.

PPHR: I understand that about 10% of a population may be carriers for meningitis B, but that most of these carriers will never contract the bacteria. Could you explain how carriers factor into outbreak response?

PATEL: Carriage is really interesting. We have so much left to understand about carriage. The basic statistic is that 5-10% of people are carriers of meningitis b, and less than 1% of the carriers actually go on to develop invasive disease. So, what makes one person more likely to develop invasive disease than the other? There are behavioral things, such as the pubs and the bars and all those kinds of things, but there are probably other kinds of factors because cases of meningococcal disease are so rare—this past year we had something like 565 cases of meningococcal disease across all the ages, and we usually get about 50 cases of meningitis b among adolescents. It’s really hard to understand what makes one person more susceptible than somebody else, but it’s probably a combination of factors.

PPHR: Do you think Princeton will provide Trumenba to the community in addition to the Bexsero vaccination clinics of previous years? Would there be any advantage to having both vaccines?

PATEL: I would have to defer that to Princeton, I’m not sure what their plans are. This all just happened two days ago, so I think a lot of people are figuring out their strategy now.

I don’t think [there is an advantage to both]. Firstly, they’re not interchangeable, meaning that you can’t start one series and continue with doses from the other brand. I think as we review the pending data, what the CDC is likely to say is that, when two vaccines are very similar, one is not favorable to the other. As we look further into the data that still under review for both vaccines we will have a better answer to that question.

PPHR: When do you think the meeting will determine that?

PATEL: Ultimately, when the data becomes available. The meningococcal workgroup, which includes the chair of the ACIP [and is composed of] the leading experts on meningitis, meets monthly. The ACIP meetings are three times a year. Right now, we don’t know because there is a substantial amount of data that is yet to be reviewed because the process is very much ongoing.