With a variety of new vaccines technology in play - such as cell-culture production, novel adjuvants and reverse vaccinology - Novartis' fledgling vaccines unit is at the cutting edge of vaccine development and could become a major player in the revitalized vaccine field.

Although it is a recent entrant to the vaccines market, the company has been a quick adopter of new vaccine technology. Novartis added its vaccine division in 2006 through the acquisition of Chiron (¹ Also see "Novartis Catches Flu Fever: Second Bid Nets Chiron" - Pink Sheet, 7 November, 2005., p.15). (see chart: ² Another Look At The Novartis/Chiron Deal...) To further expand its vaccine portfolio, Novartis partnered with discovery company Intercell in July, providing access to more than 10 projects in preclinical and early-stage development.

So far the firm only has two vaccines licensed in the U.S., Fluvirin for seasonal influenza and the rabies vaccine RabAvert (both gained via Chiron), but it has a much more substantial presence overseas - with a full portfolio of childhood, flu and developing world products.

Novartis' pipeline is replete with technologies that hold the promise of creating novel products that have advantages over traditional vaccines.

In an interview with "The Pink Sheet," Novartis Vaccines & Diagnostics Global Head for Vaccine Research Rino Rappuoli highlighted the benefits of new technologies - like reverse vaccinology - and explained how they will be used to establish Novartis as a vaccine powerhouse.

This is an exciting time for vaccine research, Rappuoli says. "We are really on the edge. My prediction is that in 10 to 15 years, what is now 100 percent of the vaccine world will be a small fraction [of available vaccines] and new types of vaccines will be coming, vaccines which will not be developed just following the strength of the Pasteur principles."

Much like the stimulus provided by genetic mapping, Rappuoli said, moving forward scientifically will require "a paradigm shift. We think that we are on the verge of discovering how to do these things."

Rappuoli believes new frontiers in technology, genomics, immunology, and development of novel adjuvants are the future of vaccinology.

"We do have a bright future. We can make vaccines against the majority of infectious diseases, maybe against chronic diseases like cancer."

Reverse vaccinology, for example, will produce more effective vaccines faster and provide novel antigens to attack diseases science currently cannot prevent, according to Rappuoli, who pioneered the approach.

The first progress with reverse vaccinology has been with meningococcus B (MenB), a target that had been impossible to hit with existing methods, Rappuoli explained. "Back in the middle 1990s, I tried several times to find novel ways to make a vaccine for meningococcus B, but eventually I shut down all the projects because I could not find a way with the technologies available at that time to develop a vaccine. I thought it was beyond the reach of the technologies we had," he said.

However, Craig Venter's publication of the genome of haemophilus influenza changed the parameters. "We basically had failed using the Pasteur principles to make the vaccine, where you start from the microorganism. We thought that instead of starting from the microorganism, we could start from the genome and go backwards and design the vaccine."

In 2000, while at Chiron, Rappuoli developed his new approach, called reverse vaccinology in which, using the whole genome, vaccine candidates are selected based on highly conserved antigen sequences, proteins for candidates are expressed, and immunogenicity is tested in animal models.

"We started to use the information [from the genome] to see whether we could predict antigens to be used for vaccines," he said.

The first successful application of reverse vaccinology was in meningococcus B, a disease that had eluded vaccine development for over 40 years. The product was created as a pilot of sorts - as a public health experiment in response to an epidemic in New Zealand. With the proof of principle in hand, Novartis has shifted its focus to crafting a MenB vaccine that would work for global strains.

Conventional vaccines were not able to circumnavigate the unique property of MenB - that "our immune system sees it as a self-antigen and does not recognize it, so you cannot follow the strategy that we use for the other four [meningococcus serotypes] to make a vaccine for MenB," Rappouli said.

He identified five unknown proteins - one which bound only human factor H (explaining lack of results in previous animal studies) - and created a pentavalent vaccine against MenB.

"The best vaccine up to that point was going to cover at best 20 percent [of global MenB strains]," Rappuoli said. "Our vaccine, made by the recombinant proteins, covered 78 percent. So the genome allowed us to make a big jump."

When In Doubt, Add An Adjuvant

To get higher coverage, Rappuoli tested the vaccine with an adjuvant, which allows for cross-protection against drifting and current strains.

The use of vaccine adjuvants, substances added to a vaccine to improve the immune response, has become a common trend in vaccine development. Adjuvants make vaccines more effective at lower doses. Chiron's proprietary adjuvant, MF-59, has greatly improved efficacy in Novartis vaccines like seasonal influenza Fluad and pandemic influenza Focetria . Similarly, GSK is touting the benefits of its proprietary adjuvant that is used in its HPV vaccine Cervarix , which it maintains will grant benefits versus Merck's Gardasil (³ Also see "Vaccines And Advair Keep GSK’s Earnings Steady Despite Avandia Losses" - Pink Sheet, 5 November, 2007., p. 5).

In Novartis' MenB vaccine, the MF59 adjuvant worked; the recombinant protein vaccine with adjuvant was able to induce immunity in up to 97 percent of global strains the group tested.

Phase I/II clinical testing of the MenB vaccine has been done in adolescents and Novartis is now conducting Phase II tests in infants, with data expected by the end of the year. The firm is also awaiting immunogenicity data that it hopes will come out by year-end. "If the results continue to be as good as they have been so far, we'll very likely start a Phase III trial - which means that maybe in two to three years we may have a vaccine to eliminate meningococcus B," Rappuoli said.

"Reverse vaccinology has allowed us to make a big step forward. Now we have orders of magnitude more antigens available ... [which] is a gold mine. This is our future," Rappuoli asserted.

In The End, It's All Structure

In addition to genomics, antigen structure will be a critical part of future vaccine development. Surface antigen variability greatly affects the vaccine's success rate, Rappuoli noted, so understanding antigens is essential to developing an effective vaccine.

Antigens on the polio virus never change, so one vaccine will protect humans for a lifetime. Influenza antigens vary annually, hence the yearly flu vaccine. A big problem comes when antigens change every day, like on HIV.

Rappuoli focused on HIV as an example of how structural vaccinology - developing vaccines based on knowledge of antigen structure - could be a novel approach to create an effective vaccine.

Instead of looking at the virus or its components, Rappuoli says looking at the structure of antigens could provide a way around the virus and its components, as in the recent failed Merck investigational HIV vaccine V520 (see story on p. 21).

In early 2007, the journal Nature reported a vulnerable epitope site on HIV recognized by the human antibody b12. The epitope is present on every HIV isolate, so a vaccine inducing an antibody to this epitope could in theory prevent HIV, Rappuoli pointed out.

Like MenB, however, "the immune system doesn't see [the epitope]. The immune system sees all the other epitopes, but it doesn't see this one. In order to understand how we can convince the immune system to see these things, we need to understand what kind of glasses the immune system uses."

A high-throughput assay to determine the structure of immunodominant and non-immunodominant epitopes, as well as understanding the rules of the immune system, Rappuoli said, could transform HIV prevention.

"Today we do not start vaccine development programs without knowing the genome. In 10 years we should not start a vaccine program without knowing the structure of the antigen," he stated.

Pipe(line) Dreams

A vaccine for HIV, currently in preclinical development in collaboration with NIH, is one of the many vaccines in Novartis' pipeline. Also in the preclinical phase is a Hepatitis C vaccine.

Several of Novartis' vaccine pipeline opportunities are coming from its latest deal with Intercell. Of particular interest, Rappuoli said, are Intercell's pseudomonas, pneumococcus, Japanese encephalitis and Hepatitis C vaccines, all in various stages of clinical trials. "We have a number of projects we are very excited about" internally as well, including Group A and B streptococcus and staphylococcus candidates, he said.

In addition to the MenB vaccine, Novartis has a tetravalent MenACYW vaccine, Menveo , in Phase III. "Hopefully we'll file early next year," Rappuoli said. "It could be in the U.S. first, because in MenACYW the U.S. is more advanced than Europe because there's already [Sanofi Pasteur's MenACYW vaccine] Menactra on the market. The concept of the vaccine is already there."

"The big difference between our vaccine and Menactra," Rappuoli continued, "is that our vaccine will be the only one for infants." Menactra is only indicated for children over 2 years old.

Novartis just released clinical data for Menveo in infants, showing broad immune response in infants as young as six months.

Quinvaxem , a pentavalent vaccine against diphtheria, tetanus, pertussis, hepatitis B, and Hib, co-developed with Crucell, has been pre-qualified by the World Health Organization and is in registration in several countries (not including the U.S. or Europe).

Novartis was awarded a contract in November 2006 to supply the U.S. government stockpile with a pre-pandemic influenza vaccine against H5N1. Rappuoli hopes the vaccine, which has been filed in Europe as Aflunov , will be approved next year, and estimates a U.S. filing in September 2008. The pandemic flu vaccine Focetria is already approved in Europe.

Waiting For A Cultural Revolution

Another Novartis vaccine, Optaflu - just approved in Europe - is the first cell culture-based seasonal influenza vaccine available. Cell culture-based production is gaining favor with companies and regulators because it is faster, more reliable, more reproducible, and purer than conventional egg-based methods.

Other firms, like Sanofi Pasteur - who recently announced initiation of Phase II trials for its cell culture-based seasonal influenza vaccine in the U.S. - have also jumped on the cellular bandwagon, but Novartis holds the lead.

Novartis estimates a U.S. submission for Optaflu in 2008, and FDA approval would be positive for the space, as "once the new technology is in place you can use it to advance the field, to improve vaccines," Rappuoli said.

Cell culture technology has also garnered attention as the world prepares for pandemic flu, since it will shorten the time from manufacturing to distribution, which will be critical during a pandemic.

Pandemics, Plants, and Portfolios

A pre-pandemic vaccine would negate the need for stockpiling, Rappuoli says: "If you do it well, the pandemic will never happen because you'll prevent it."

Stockpiling will "never be fast enough" in a pandemic, Rappuoli believes.

"You have to wait for WHO to declare the pandemic, then you pick the strain that is causing the pandemic, then you manufacture the vaccine, and then you vaccinate people - that strategy is not going to work. I call that the strategy to vaccinate survivors."

Novartis received a $220 million contract from the Department of Health and Human Services to build a cell culture-based plant in North Carolina, complementing the cell culture capabilities at their Liverpool, U.K. and Marburg, Germany facilities (⁴ Also see "Novartis’ New Vaccine Division Takes On Evolving Market" - Pink Sheet, 31 July, 2006., p. 11). Rappuoli estimates the plant will roll out commercially available vaccines in 2012.

Catch The (Yellow) Fever

Novartis is also rolling out its Novartis Vaccine Institute for Global Health, a "new non-profit initiative completely dedicated to developing effective and affordable vaccines for commercially neglected infectious diseases in developing countries." The NVIGH will complement Novartis' Institute for Tropical Diseases, which develops drugs for impoverished countries. In September, Allan Saul, formerly a malaria vaccine researcher at NIH, was hired as CEO of NVIGH, which is expected to open in February 2008.

- Becky Jungbauer (r.jungbauer@elsevier.com)

Novartis Vaccines Unit Looks To Make Its Presence With New Technologies

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