In the world of pharmaceuticals, vaccines have largely beenislands unto themselves.
Although purely prophylactic in nature until recently,vaccine clinical trials were different than those for typical pharmaceutics, asthey relied largely on surrogate endpoints in healthy individuals to determineefficacy, rather than direct endpoint improvements in unhealthy individuals.Likewise, the goal of treatment was ironically to give the patient a mild formof the disease, at least from an immunological perspective, so the body couldlearn 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 presentthe "active" component of the vaccines and its supporting adjuvant players. Theexpanding market potential of the developing world has shone a brighter lighton issues exclusive to these regions. Even the canonical paradigm of"one-shot-fits-all" has fallen by the wayside with an expanding variety ofdelivery vehicles—and yes, even a personalized approach.
To discuss some of these changes and how they have impactedone vaccine producer in particular, ddnrecently spoke with Jim Tartaglia, vice president and the North American headof Sanofi Pasteur's New Vaccine unit.
ddn: We recently published two features on personalizedmedicine—the idea of individualizing treatment to the level of the patientbased on his or her biomolecular makeup. A similar concept—"vaccinomics"—isdeveloping in immunization, and would seem to fly in the face of thetraditional "one-vaccine-fits-(practically)-all" paradigm.
Tartaglia:Vaccine development has traditionally been an empiric science, where youprocess through multiple steps to build vaccines and try to find an effectivecandidate. But it is also an evolving science that is relying more onconvergent technologies which allow us to understand the immune system as awhole—which may, in the long run, allow us to rely less on surrogate markers ofefficacy when licensing new vaccines.
We're amassing data on a number of different fronts, bothwith respect to functional immune responses and protective profiles, to give usa more complete and comprehensive understanding of what's underlying aprotective immune response, because you always need to relate that to theclinical outcome—whether it be protection against or modulation of infection,or some kind of therapeutic clinical outcome. I really see the systems biologyapproach to immune response and linking it to clinical as being something thatis going to be more attainable in the short term in the more therapeuticsetting.
I see immunotherapy one day being an important component ofdisease management in various settings. For example, the immune response is atthe crux of a lot of disease states, including allergy, asthma, autoimmunity,potentially diabetes and cancer. There you have a greater opportunity to reallylink your immune response with a therapeutic outcome in a more manageabletimeframe. I see vaccinomics as something that could be key in the therapeuticsense, in being able to dissect out what a protective outcome is and whichpopulations 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 infectiousagents. A lot of people are trying to link these observations now from asystems biology approach to outcomes from a clinical setting and providing abetter understanding of the immunobiology.
For instance, Rafick-Pierre Sécaly [of Florida's Vaccine& Gene Therapy Institute] has just published a couple of papers in thisarea, both with respect to dengue and tuberculosis, that could be applied toany type of clinical development for such vaccines, even as a preventive, butyou won't have that validated until you actually have a vaccine. That's whereyou need the tight understanding of the basic biology and marrying that toclinical development and efficacy outcomes and endpoints, so you can validatethe associations from the various settings that are done more upstream.
Vaccinomics and systems biology approaches are key. We areinvesting in these areas and trying to link them to outcomes in our clinicaldevelopment efforts. It does take some planning, making sure that you can amassthe right samples and assess them in the appropriate way. But you need thatlinkage, and it will be important in the future to better inform us and enhanceour probability of success, whether it's in the prophylactic or immunetherapeutic setting.
ddn: It appears that despite the availability of a hundred ormore different vaccine adjuvants, most commercial vaccines seem to use only asmall subset of adjuvants.
Tartaglia: Anylicensed adjuvant in a vaccine formulation today is in the context of thatspecific formulation. There are no generic licenses from an adjuvantperspective. So, there is aluminum (whether aluminum phosphate or aluminumhydroxide), MF59 in the flu vaccine from Novartis and the GlaxoSmithKline PLC(GSK) formulation in Cervarix. There are a number of adjuvant formulations thatare under development, whether they be oil-and-water emulsions, squalene orothers that contain known immunomodulators, like the TLR agonists, but none ofthose are in-licensed products yet.
Most of the easy targets have been taken care of, and weknow the tougher targets have profiles that we really feel are going to beimportant from an adjuvant perspective. We are going to need novel adjuvants tonot just elicit the appropriate response, but also to have a durable immuneresponse. That's especially true in prophylaxis—particularly when thinking ofthings that concern the developing world, where you're going to need a regimenthat is cost-effective for these governments to deploy.
But novel adjuvants come with a two-edged sword. You have toremember that you're going to be using these formulations in healthyindividuals, so the safety profile has to match that expectation from arisk-benefit perspective. Now, with adjuvants and immune modulators in othersettings like cancer therapeutics, the risk/benefit is totally different. Thatbeing said, in all cases, one really needs to know the mechanism of action ofthe adjuvant, how it's actually enhancing immune responses, and have a handleon any untoward events.
Cervarix was licensed with the adjuvant ASO4, but that camewith a price for GSK. They have significant post-license commitments aroundsafety, especially from an autoimmune perspective. So you really do need toknow your product; you need to know the mechanism of action. But even withthat, as novel adjuvants become licensed, especially in the prophylacticsetting, there's going to be significant post-license commitments looking atlong-term safety in people that receive the vaccine.
Obviously, we're working on adjuvants—with our own and withothers—in various areas of our new vaccine pipeline.
ddn: Sanofi Pasteur has made its mark in the control ofinfectious disease, but a lot of interest in recent years has shifted to thedevelopment of vaccines targeting cancer.
Tartaglia: BeforeI was in Pennsylvania, I headed R&D at the Toronto site for 13 years, wherewe had a cancer vaccine project. The program was focused on colorectal cancerand melanoma. We went to Phase II in both settings and we did not meet ourendpoints, either because of enrollment sensitivities or from a clinicaloutcome, so we dropped the program.
I think in some ways, it was a bit premature to have such aprogram. 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 wewere a bit ahead of our time. The world is awaiting the GSK results with itsMAGE vaccine in lung cancer, which should come out relatively soon, and we knowthat Provenge from Dendreon was the first cancer vaccine that was licensed inthe United States.
The difficulty is you're going to need to develop yourtreatment in the context of standard of care, and you really need to showimprovements in overall survival. You're going to have to differentiateyourself from what's out there already. You really have to demonstrate thatthere's true medical value to what you bring forward above what's currentlyused.
Not all cancers are the same within a person or betweenpatients. Being able to better predict who will or will not respond, and beingable to better modulate immune responses—both from a positive and negativeperspective—will be key.
Maybe we didn't know enough at the time. I do believe weadded to the field, but we didn't add a product to the field that can helpcancer patients. I think that some of the things we did, in combination withsome of the evolutions that I just mentioned, are going to be important forpeople—maybe even us some day—in developing these products such that they are avalue-added component to disease management, at least of some cancers. One canthink of those things even in the context beyond cancer, in areas such asautoimmunity, transplantation, diabetes, etc.
ddn: Another area of intense vaccine research is in theprevention and treatment of HIV/AIDS.
Tartaglia: Ithink I'm the only person still in the company who was originally involved inour efforts on HIV that started in the 1990 timeframe. I was responsible forRV144, which was the Thai efficacy study that we were involved in, published threeyears ago [in the New England Journal ofMedicine]. This was the first vaccine regimen that was shown to be able toprotect against HIV infection—although only at modest levels—and certainly notsomething that was licensable.
At that point, I put forward a strategy that would befocused on substantiating and extending upon the RV144 results, and I starteddiscussions that led to the formation of P5 (Pox-Protein Public-PrivatePartnership). 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 P5is with Novartis.
One of the reasons I wanted to partner with Novartis was theRV144 results. The one-year observation suggested we had around 60-percentprotection, but that protection waned with time. At the three-year post-vaccinepoint, we were down to 31.6 percent. I knew Novartis was involved at some levelin HIV vaccine development, and we had partnered with them before. They knewhow to produce the recombinant envelope component, but they also had MF59,which had a significant human safety database and was in-licensed. I thoughtthat this would be a better adjuvant on top of the aluminum to give us a moredurable response with the prime-boost regimens we were looking at.
We have an agreement with Novartis, but then became part ofP5, which contains the Gates Foundation, the NIH, the HIV Vaccine Trial Networkand the U.S. Army. Our focus is on extending the observations of RV144 to theRepublic of South Africa, where we are looking to move to Phase IIb, whichcould start in the 2015 timeframe, with the appropriately designed vaccinesthat look to mimic, as much as possible, what we used in RV144.
So there's a development component and a research-trackcomponent, because we know that, as we speak today, although RV144 did providesome signals from a biomarker or surrogate immune perspective, those have notbeen fully validated. They are more hypothesis-driven. They'll form the basisof some of the questions we ask as we move forward with subsequent clinicaltrials.
There's a clinical research perspective, too, understandingthat HIV vaccine clinical development as it exists today is an iterativeprocess we need to build. We know that if we're able to achieve 50- to60-percent protection in South Africa in the development track, this will leadto a license there and perhaps a deployable vaccine. Not a home run, by anymeans. 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, newregimens and new ways of looking at these things. In addition to having adevelopment track, we must have a clinical research track. That way, we canbring these new elements forward and test them from a clinical perspective, butalso be able to better understand them with systems biology solutions, andperhaps more firmly nail down elements around a biomarker of protection from avaccine-induced perspective.
We are also looking to build off what we did in Thailand topotentially move to a population indication that could be licensable anddeployable in Thailand. We've started some additional studies in Thailand tobetter understand the immune response and things around protective profilesthat we talked about earlier. Hopefully, each of the elements will inform theothers so that we can make decisions and move the field forward.
ddn: Sanofi Pasteur has an extensive portfolio of vaccinesagainst well-characterized infectious diseases of the developed world, but whatabout emerging diseases coming from the developing world?
Tartaglia: From abusiness perspective, we are no. 1 in emerging markets, and facilitatingvaccine 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 somedisappointing but promising results. We've been working on dengue for 20 yearsor more. It's the first vaccine in the last stage of clinical development—PhaseIII clinical trials in Latin America—so this is an important program.
The other areas that are important now in our portfolio arepneumonia caused by Strep. pneumoniae.We're working on a conserved-protein approach, and have been partnering and arelooking to partner to bring that to a proof-of-concept study. We're currentlyin Phase I in Bangladesh in infants, and have just completed enrollment. And wehave a tuberculosis vaccine program in infants and adolescents, and that ispartnered with others. These are areas where one clearly needs to partner.
With infectious disease becoming more and more a globalpublic health concern, building the clinical and regulatory infrastructures inthese countries has become more important. Everything that we do in this regardgoes toward that capacity building. I think that some of the things we did withHIV in Thailand, for instance, in preparing for RV144 really strengthened theThai FDA.
If you think about the prior vaccine distribution paradigm,things were licensed first in the developed world and then 10 to 15 yearslater, after recouping R&D investments, people started to move to licensein other parts of the world. So the national regulatory agencies in thesecountries were always dependent on the developed world regulators as theprimary review.
Now, as we're talking about dengue, as we're talking aboutHIV, that's not going to be the case, so the local regulatory agencies have tobe competent in this regard. Through RV144, working with the Thai Ministry ofHealth, the Thai FDA and the U.S. Army, we sought to improve the strength ofthe Thai FDA in being able to review primary applications. I think thatactually paid forward and they were able to apply these learnings to ourapplication for Japanese encephalitis vaccine that is now licensed there.
The capacity building really helps in facilitating vaccineR&D and the ultimate implementation and deployment of programs around thosevaccines.
The more we do to bolster public health in these countriesbolsters the economies of these countries, and that builds stronger marketsaround the world for everybody. There is also the need to share risk, shareinvestment and share the benefits to be able to effectively develop vaccines inthese areas of the world, especially when thinking of our shareholders. We arein business.
The ROI is low, but that's why you have partners. You shiftthe equation a bit and it's more helpful. Each of the pieces has to be lookedat as a whole, but whether it's in the upstream or downstream front, we'relooking to public health partners (e.g.,UNICEF, GAVI). There's a push-pull mechanism, and for all the differentindications, the different situations, you have different partners that youlook 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 partnerto maximize efforts to prepare for vaccination programs, so we joined forceswith these international groups to raise awareness and to move denguevaccination to a higher priority as necessary. But it also depends on theresults of the study. It is similar with all of those things, whether talkingabout existing vaccines or ones under development.
In 2009, we acquired Shantha Biotechnics, an Indian biotechcompany. They've been working to develop and market several pediatric vaccinesincluding the first recombinant Hep B vaccine that was produced in India. We'rethinking about how to utilize them from an R&D perspective, but also from amanufacturing and deployment perspective in such regions.
ddn: The creation of vaccines and immunization programs for thedeveloping world provides unique challenges that are not commonly seen withdeveloped world immunization programs.
Tartaglia:Thermostability is a key component, and there are a number of programs that areunderway here, both for existing and newly developed vaccines. Anything you cando to eliminate or reduce the reliance on cold chain and extend shelf lives soyou can utilize your available doses more effectively is key. I know the GatesFoundation and other funding organizations are interested in those things. Wework with these groups to look at that from a competitive and precompetitiveperspective.
Depending on the device, there is also a cost-of-goodsquestion. We were the first to license a vaccine with an intradermal device inEurope and Australia with VaxiGrip ID and then in the United States withFluzone ID. Here, the business case is more around convenience, as opposed toeffectiveness of vaccine.
ddn: Speaking of devices, there seems to have been a lot ofactivity in recent years focused on the delivery mechanisms for variousvaccines (e.g., IM vs. ID vs. oralvs. intranasal).
Tartaglia: Someof these things are going to be more for differentiation. I don't see wherewhat devices are available would lead to a vaccine that is more potent. Perhapsin the future, that will be the case. How you use that and where you use thatwill depend upon the situation at hand.
Intradermal had been used for rabies in some parts of theworld, but always with the Mantoux method, which was not always reliable andneeded extensive training for administrators. That's where we partnered withBecton Dickinson on the intradermal device.
Same with intranasal, where the goal was getting it to themucosal surfaces more effectively, the areas where the viral portal of entry.One also has to look at convenience, compliance and reliability. It's not agiven, but it has to be explored.
Our ability to promote and adapt to change has beenessential. 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'reinvesting a lot in innovation, both to facilitate vaccine R&D as well asdeployment.
Technologies such as genomics, immunology, informatics andmodeling will allow us to better appreciate the overall immune response—thesystems biology—so that we become less empiric. I don't think you can everdismiss the empiric piece, because you're going to have to do the clinicaltrials, but at least it allows us to become more predictive. It's easy to sayit's going to be a slam-dunk, but it's not.
We just invested in acquiring VaxDesign, a Florida-basedbiotech that has a system called Mimic, which is essentially a lymph node in atest tube, but with great automation behind it. One can use these in-vitro human immune systems to maybeask different questions and get away—not totally, but to some extent—from theanimal models that have not been predictive. This helps us gain a greaterappreciation and handle on probabilities for success in our clinicaldevelopment plan.
All of those elements come together around the key messageof trying to use a more informed basis of progressing our development programs.
