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No vaccine is an island
January 2013
by Randall Willis  |  Email the author


In the world of pharmaceuticals, vaccines have largely been islands unto themselves.  
Although purely prophylactic in nature until recently, vaccine clinical trials were different than those for typical pharmaceutics, as they relied largely on surrogate endpoints in healthy individuals to determine efficacy, rather than direct endpoint improvements in unhealthy individuals. Likewise, the goal of treatment was ironically to give the patient a mild form of the disease, at least from an immunological perspective, so the body could learn to defend itself.  
Recently, however, that scenario has started to change. Vaccinology is supplementing the preventative with the therapeutic. High-profile safety issues have forced researchers to look at how they present the "active" component of the vaccines and its supporting adjuvant players. The expanding market potential of the developing world has shone a brighter light on issues exclusive to these regions. Even the canonical paradigm of "one-shot-fits-all" has fallen by the wayside with an expanding variety of delivery vehicles—and yes, even a personalized approach.  
To discuss some of these changes and how they have impacted one vaccine producer in particular, ddn recently spoke with Jim Tartaglia, vice president and the North American head of Sanofi Pasteur's New Vaccine unit.  
ddn: We recently published two features on personalized medicine—the idea of individualizing treatment to the level of the patient based on his or her biomolecular makeup. A similar concept—"vaccinomics"—is developing in immunization, and would seem to fly in the face of the traditional "one-vaccine-fits-(practically)-all" paradigm.  
Tartaglia: Vaccine development has traditionally been an empiric science, where you process through multiple steps to build vaccines and try to find an effective candidate. But it is also an evolving science that is relying more on convergent technologies which allow us to understand the immune system as a whole—which may, in the long run, allow us to rely less on surrogate markers of efficacy when licensing new vaccines.  
We're amassing data on a number of different fronts, both with respect to functional immune responses and protective profiles, to give us a more complete and comprehensive understanding of what's underlying a protective immune response, because you always need to relate that to the clinical outcome—whether it be protection against or modulation of infection, or some kind of therapeutic clinical outcome. I really see the systems biology approach to immune response and linking it to clinical as being something that is going to be more attainable in the short term in the more therapeutic setting.  
I see immunotherapy one day being an important component of disease management in various settings. For example, the immune response is at the crux of a lot of disease states, including allergy, asthma, autoimmunity, potentially diabetes and cancer. There you have a greater opportunity to really link your immune response with a therapeutic outcome in a more manageable timeframe. I see vaccinomics as something that could be key in the therapeutic sense, in being able to dissect out what a protective outcome is and which populations are able to mount such a response.  
With respect to thinking about prophylaxis and vaccinomics, a lot is being done looking at different disease states caused by infectious agents. A lot of people are trying to link these observations now from a systems biology approach to outcomes from a clinical setting and providing a better understanding of the immunobiology.  
For instance, Rafick-Pierre Sécaly [of Florida's Vaccine & Gene Therapy Institute] has just published a couple of papers in this area, both with respect to dengue and tuberculosis, that could be applied to any type of clinical development for such vaccines, even as a preventive, but you won't have that validated until you actually have a vaccine. That's where you need the tight understanding of the basic biology and marrying that to clinical development and efficacy outcomes and endpoints, so you can validate the associations from the various settings that are done more upstream.  
Vaccinomics and systems biology approaches are key. We are investing in these areas and trying to link them to outcomes in our clinical development efforts. It does take some planning, making sure that you can amass the right samples and assess them in the appropriate way. But you need that linkage, and it will be important in the future to better inform us and enhance our probability of success, whether it's in the prophylactic or immune therapeutic setting.  
ddn: It appears that despite the availability of a hundred or more different vaccine adjuvants, most commercial vaccines seem to use only a small subset of adjuvants.  
Tartaglia: Any licensed adjuvant in a vaccine formulation today is in the context of that specific formulation. There are no generic licenses from an adjuvant perspective. So, there is aluminum (whether aluminum phosphate or aluminum hydroxide), MF59 in the flu vaccine from Novartis and the GlaxoSmithKline PLC (GSK) formulation in Cervarix. There are a number of adjuvant formulations that are under development, whether they be oil-and-water emulsions, squalene or others that contain known immunomodulators, like the TLR agonists, but none of those are in-licensed products yet.  
Most of the easy targets have been taken care of, and we know the tougher targets have profiles that we really feel are going to be important from an adjuvant perspective. We are going to need novel adjuvants to not just elicit the appropriate response, but also to have a durable immune response. That's especially true in prophylaxis—particularly when thinking of things that concern the developing world, where you're going to need a regimen that is cost-effective for these governments to deploy.
But novel adjuvants come with a two-edged sword. You have to remember that you're going to be using these formulations in healthy individuals, so the safety profile has to match that expectation from a risk-benefit perspective. Now, with adjuvants and immune modulators in other settings like cancer therapeutics, the risk/benefit is totally different. That being said, in all cases, one really needs to know the mechanism of action of the adjuvant, how it's actually enhancing immune responses, and have a handle on any untoward events.  
Cervarix was licensed with the adjuvant ASO4, but that came with a price for GSK. They have significant post-license commitments around safety, especially from an autoimmune perspective. So you really do need to know your product; you need to know the mechanism of action. But even with that, as novel adjuvants become licensed, especially in the prophylactic setting, there's going to be significant post-license commitments looking at long-term safety in people that receive the vaccine.  
Obviously, we're working on adjuvants—with our own and with others—in various areas of our new vaccine pipeline.
ddn: Sanofi Pasteur has made its mark in the control of infectious disease, but a lot of interest in recent years has shifted to the development of vaccines targeting cancer.  
Tartaglia: Before I was in Pennsylvania, I headed R&D at the Toronto site for 13 years, where we had a cancer vaccine project. The program was focused on colorectal cancer and melanoma. We went to Phase II in both settings and we did not meet our endpoints, either because of enrollment sensitivities or from a clinical outcome, so we dropped the program.  
I think in some ways, it was a bit premature to have such a program. I would have done it a bit different today. There are newer tools, newer ways to modulate the immune response that have come forward. Maybe we were a bit ahead of our time. The world is awaiting the GSK results with its MAGE vaccine in lung cancer, which should come out relatively soon, and we know that Provenge from Dendreon was the first cancer vaccine that was licensed in the United States.  
The difficulty is you're going to need to develop your treatment in the context of standard of care, and you really need to show improvements in overall survival. You're going to have to differentiate yourself from what's out there already. You really have to demonstrate that there's true medical value to what you bring forward above what's currently used.  
Not all cancers are the same within a person or between patients. Being able to better predict who will or will not respond, and being able to better modulate immune responses—both from a positive and negative perspective—will be key.   Maybe we didn't know enough at the time. I do believe we added to the field, but we didn't add a product to the field that can help cancer patients. I think that some of the things we did, in combination with some of the evolutions that I just mentioned, are going to be important for people—maybe even us some day—in developing these products such that they are a value-added component to disease management, at least of some cancers. One can think of those things even in the context beyond cancer, in areas such as autoimmunity, transplantation, diabetes, etc.
ddn: Another area of intense vaccine research is in the prevention and treatment of HIV/AIDS.  
Tartaglia: I think I'm the only person still in the company who was originally involved in our efforts on HIV that started in the 1990 timeframe. I was responsible for RV144, which was the Thai efficacy study that we were involved in, published three years ago [in the New England Journal of Medicine]. This was the first vaccine regimen that was shown to be able to protect against HIV infection—although only at modest levels—and certainly not something that was licensable.  
At that point, I put forward a strategy that would be focused on substantiating and extending upon the RV144 results, and I started discussions that led to the formation of P5 (Pox-Protein Public- Private Partnership). Since its inception, our HIV program has been partnered with academia, not-for-profit organizations, various funders (e.g., the Gates Foundation, the National Institutes of Health (NIH), the U.S. Army and the Thai Ministry of Health) and other companies (e.g., VaxGen, Merck, Novartis). The P5 is with Novartis.  
One of the reasons I wanted to partner with Novartis was the RV144 results. The one-year observation suggested we had around 60-percent protection, but that protection waned with time. At the three-year post-vaccine point, we were down to 31.6 percent. I knew Novartis was involved at some level in HIV vaccine development, and we had partnered with them before. They knew how to produce the recombinant envelope component, but they also had MF59, which had a significant human safety database and was in-licensed. I thought that this would be a better adjuvant on top of the aluminum to give us a more durable response with the prime-boost regimens we were looking at.  
We have an agreement with Novartis, but then became part of P5, which contains the Gates Foundation, the NIH, the HIV Vaccine Trial Network and the U.S. Army. Our focus is on extending the observations of RV144 to the Republic of South Africa, where we are looking to move to Phase IIb, which could start in the 2015 timeframe, with the appropriately designed vaccines that look to mimic, as much as possible, what we used in RV144.  
So there's a development component and a research-track component, because we know that, as we speak today, although RV144 did provide some signals from a biomarker or surrogate immune perspective, those have not been fully validated. They are more hypothesis-driven. They'll form the basis of some of the questions we ask as we move forward with subsequent clinical trials.  
There's a clinical research perspective, too, understanding that HIV vaccine clinical development as it exists today is an iterative process we need to build. We know that if we're able to achieve 50- to 60-percent protection in South Africa in the development track, this will lead to a license there and perhaps a deployable vaccine. Not a home run, by any means. Obviously, what we want to move towards is a globally relevant vaccine, one that's broadly protective, and we're not there yet.  
We're going to have to explore new technologies, new regimens and new ways of looking at these things. In addition to having a development track, we must have a clinical research track. That way, we can bring these new elements forward and test them from a clinical perspective, but also be able to better understand them with systems biology solutions, and perhaps more firmly nail down elements around a biomarker of protection from a vaccine-induced perspective.  
We are also looking to build off what we did in Thailand to potentially move to a population indication that could be licensable and deployable in Thailand. We've started some additional studies in Thailand to better understand the immune response and things around protective profiles that we talked about earlier. Hopefully, each of the elements will inform the others so that we can make decisions and move the field forward.  
ddn: Sanofi Pasteur has an extensive portfolio of vaccines against well- characterized infectious diseases of the developed world, but what about emerging diseases coming from the developing world?  
Tartaglia: From a business perspective, we are no. 1 in emerging markets, and facilitating vaccine R&D and deployment for the future in such areas is very important. We are at the forefront of developing a dengue vaccine. We 've just had some disappointing but promising results. We've been working on dengue for 20 years or more. It's the first vaccine in the last stage of clinical development—Phase III clinical trials in Latin America—so this is an important program.  
The other areas that are important now in our portfolio are pneumonia caused by Strep. pneumoniae. We're working on a conserved- protein approach, and have been partnering and are looking to partner to bring that to a proof-of-concept study. We're currently in Phase I in Bangladesh in infants, and have just completed enrollment. And we have a tuberculosis vaccine program in infants and adolescents, and that is partnered with others. These are areas where one clearly needs to partner.  
With infectious disease becoming more and more a global public health concern, building the clinical and regulatory infrastructures in these countries has become more important. Everything that we do in this regard goes toward that capacity building. I think that some of the things we did with HIV in Thailand, for instance, in preparing for RV144 really strengthened the Thai FDA.
If you think about the prior vaccine distribution paradigm, things were licensed first in the developed world and then 10 to 15 years later, after recouping R&D investments, people started to move to license in other parts of the world. So the national regulatory agencies in these countries were always dependent on the developed world regulators as the primary review.  
Now, as we're talking about dengue, as we're talking about HIV, that 's not going to be the case, so the local regulatory agencies have to be competent in this regard. Through RV144, working with the Thai Ministry of Health, the Thai FDA and the U.S. Army, we sought to improve the strength of the Thai FDA in being able to review primary applications. I think that actually paid forward and they were able to apply these learnings to our application for Japanese encephalitis vaccine that is now licensed there.  
The capacity building really helps in facilitating vaccine R&D and the ultimate implementation and deployment of programs around those vaccines.
The more we do to bolster public health in these countries bolsters the economies of these countries, and that builds stronger markets around the world for everybody. There is also the need to share risk, share investment and share the benefits to be able to effectively develop vaccines in these areas of the world, especially when thinking of our shareholders. We are in business.  
The ROI is low, but that's why you have partners. You shift the equation a bit and it's more helpful. Each of the pieces has to be looked at as a whole, but whether it's in the upstream or downstream front, we're looking to public health partners (e.g.,UNICEF, GAVI). There's a push-pull mechanism, and for all the different indications, the different situations, you have different partners that you look at, and now with the Gates Foundation and the investment they have, partnering with them is also important.  
When we were looking at dengue, we were looking to partner to maximize efforts to prepare for vaccination programs, so we joined forces with these international groups to raise awareness and to move dengue vaccination to a higher priority as necessary. But it also depends on the results of the study. It is similar with all of those things, whether talking about existing vaccines or ones under development.  
In 2009, we acquired Shantha Biotechnics, an Indian biotech company. They've been working to develop and market several pediatric vaccines including the first recombinant Hep B vaccine that was produced in India. We're thinking about how to utilize them from an R&D perspective, but also from a manufacturing and deployment perspective in such regions.
ddn: The creation of vaccines and immunization programs for the developing world provides unique challenges that are not commonly seen with developed world immunization programs.  
Tartaglia: Thermostability is a key component, and there are a number of programs that are underway here, both for existing and newly developed vaccines. Anything you can do to eliminate or reduce the reliance on cold chain and extend shelf lives so you can utilize your available doses more effectively is key. I know the Gates Foundation and other funding organizations are interested in those things. We work with these groups to look at that from a competitive and precompetitive perspective.  
Depending on the device, there is also a cost-of-goods question. We were the first to license a vaccine with an intradermal device in Europe and Australia with VaxiGrip ID and then in the United States with Fluzone ID. Here, the business case is more around convenience, as opposed to effectiveness of vaccine.
ddn: Speaking of devices, there seems to have been a lot of activity in recent years focused on the delivery mechanisms for various vaccines (e.g., IM vs. ID vs. oral vs. intranasal).
Tartaglia: Some of these things are going to be more for differentiation. I don't see where what devices are available would lead to a vaccine that is more potent. Perhaps in the future, that will be the case. How you use that and where you use that will depend upon the situation at hand.  
Intradermal had been used for rabies in some parts of the world, but always with the Mantoux method, which was not always reliable and needed extensive training for administrators. That's where we partnered with Becton Dickinson on the intradermal device.  
Same with intranasal, where the goal was getting it to the mucosal surfaces more effectively, the areas where the viral portal of entry. One also has to look at convenience, compliance and reliability. It's not a given, but it has to be explored.  
Our ability to promote and adapt to change has been essential. We're a company that has come together from three separate avenues, all three of which are about 100 years old. Innovation is key, and we 're investing a lot in innovation, both to facilitate vaccine R&D as well as deployment.  
Technologies such as genomics, immunology, informatics and modeling will allow us to better appreciate the overall immune response—the systems biology—so that we become less empiric. I don't think you can ever dismiss the empiric piece, because you're going to have to do the clinical trials, but at least it allows us to become more predictive. It's easy to say it's going to be a slam-dunk, but it's not.  
We just invested in acquiring VaxDesign, a Florida-based biotech that has a system called Mimic, which is essentially a lymph node in a test tube, but with great automation behind it. One can use these in-vitro human immune systems to maybe ask different questions and get away—not totally, but to some extent—from the animal models that have not been predictive. This helps us gain a greater appreciation and handle on probabilities for success in our clinical development plan.  
All of those elements come together around the key message of trying to use a more informed basis of progressing our development programs.  
Code: E011326



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