Trends in vaccine development

SPOTLIGHT ON VACCINES

How are public-private partnerships, low-cost manufacturers and new technology affecting the vaccine field?

BILL GATES is a handy person to have in your corner, which bodes well for those committed to vaccine research. In January 2010 the philanthropist called for a “decade of vaccines” and pledged US$10 billion for vaccine research and development (R&D) and distribution. The Bill & Melinda Gates Foundation funding will boost an already burgeoning field.

Although vaccines comprise a small portion of the global pharmaceutical market — 2 percent in 2010 — the industry is predicted to grow over the next few years. In the United States, demand will increase by around 7 percent annually until 2015, according to a 2011 report published by industry analysts Freedonia. “It’s probably the best growth area right now in infectious disease,” says Steve Projan, senior vice president of R&D in the innovative medicines unit at vaccine manufacturer MedImmune.

Credit: IMAGE SOURCE

The industry is being shaped by increased collaboration between the public and private sectors, the rise of low-cost vaccine manufacturers and the use of new technologies. The changes are significant for those interested in working in the field.

The three Ps

The expansion of public-private partnerships (PPPs) is “transforming the business of vaccines”, says Gates. Although the model has been around since the early 1990s, it has taken time for vaccine research to be funded in this way. Camille Locht, director of the Centre for Infection and Immunity of Lille (CIIL) at the Institut Pasteur in Lille, France, says that five years ago the prevailing system in Europe was still that of competition between the public and private sectors. “Pharmaceutical companies have realized that for difficult diseases such as TB there will probably not be a single private or public entity that will come up with the final-stage vaccine,” he says.

The vaccine field is going to enlarge substantially beyond the traditional preventive vaccine. Rafi Ahmed, Emory Vaccine Center

PPPs working in vaccines include the GAVI Alliance, the Aeras TB partnership and the International AIDS Vaccine Initiative (IAVI). CIIL is also a PPP, its partners comprising the Institut Pasteur in Lille — a private foundation — and the University of Lille, plus French public research institutes CNRS and INSERM. These meet needs not prioritised by the traditional vaccine development pipeline, with HIV a prime example. When the virus was identified in 1984, researchers were optimistic they could formulate a vaccine quickly. As HIV proved resilient, hopes for a fast response faded and by the early 1990s several research groups and companies had abandoned the search for a vaccine.

It became clear that a new model of vaccine development was needed, one that could bridge the gap between the public and private sectors and focus on the developing world. As a result, in 1996 IAVI was created with support from several foundations including the Rockefeller Foundation, plus the World Bank and other partners.

Established with just a handful of employees, IAVI now has 105 in-house research staff— around 75 percent of them with an industry background — and in April 2011 it launched a fellowship programme to recruit early-career postdocs from regions most affected by the HIV pandemic. It supports additional research staff through collaborations with more than 50 external partners and in February 2012 awarded US$875,000 to two researchers via open innovation broker NineSigma. IAVI’s recent research advances include the 2009 discovery of two human antibodies that have a strong neutralizing effect on HIV, and the launch of two phase-one clinical trials of vaccine candidates in Africa in February 2011 and December 2011. The 2009 discovery was accomplished through a collaboration with the Scripps Research Institute in the United States and other international partners.

An early lesson for the initiative was the importance of recruiting experienced leaders and managers from the vaccine industry with proven project management skills. Vice president of vaccine development Thomas Hassell, who joined IAVI from Sanofi Pasteur in 2008, says getting the right people was important because PPPs generally lack the funds to support major training programmes. “As far as possible you want the finished product,” he says. “You want people to get off to a racing start.”

A major catalyst for the increased number of PPPs is the rising cost of early R&D as identifying new vaccine targets becomes more complicated. Vaccine manufacturers are turning to external collaborators for candidates. “Developing a vaccine today is much more complex than it was 20 or 30 years ago,” explains Bruce Carpick, a biochemist in Sanofi Pasteur’s analytical R&D arm in Toronto, Canada. “It’s a natural progression for any major vaccine player to be looking to the external environment for opportunities.” External collaborators also benefit from the arrangement as it can help their research reach the market, and many government funding schemes now offer incentives for working with industry. “It’s a two-way street,” says Carpick.

There is also increasing emphasis on safety and governance surrounding vaccines. “Regulatory requirements are much more stringent now than they were in the past,” explains Carpick. “That has greatly increased complexity and cost.”

For now substantial funding continues to emerge through the PPP model, despite the economic climate. Last year the GAVI Alliance secured a five-year pledge of US$4.3 billion from its donors, exceeding its target of US$3.7 billion, and in April 2011 the German Federal Ministry for Economic Cooperation and Development (BMZ) increased its contribution to the alliance by US$20 million, which the Gates Foundation matched. New PPPs are “definitely something you’re going to see in the future,” says Carpick.

Cut-price competition

The vaccine manufacturing industry has been transformed recently. Following 30 years of takeovers during which many independent vaccine manufacturers were bought out, new players are emerging. A significant trend is the growth of low-cost manufacturers in developing countries. Companies whose vaccines have been judged by the World Health Organisation (WHO) to meet international standards of quality, safety and efficacy — known as prequalification — include the Serum Institute of India; Bharat Biotech, Panacea Biotec and Shantha Biotechnics, also based in India; Bio-Manguinhos in Brazil; and Bio Farma in Indonesia. A cholera vaccine produced by Shantha Biotechnics is being used in a pilot programme to halt the spread of the disease in Haiti. In March 2011 WHO opened the way for vaccine manufacturers in China to submit products for prequalification after being satisfied that the country’s regulatory systems were sufficiently robust. The decision coincided with news that Novartis Vaccines had bought a majority stake in Chinese vaccine manufacturer Zhejiang Tianyuan Bio-Pharmaceutical in order to expand its presence in China, the world’s third-largest vaccines market.

Rafi Ahmed, director of the Emory Vaccine Center (EVC) at Emory University in the United States, says that manufacturers in India are providing a “tremendous” public health service by producing cut-price vaccines, but still need to build their R&D capabilities. He says these companies will need to collaborate more with research institutes in the United States and Europe as well as in India in order to make progress. To this end, last month India’s Gennova Biopharmaceuticals opened a new vaccine-manufacturing facility in Pune in western India in partnership with two Seattle-based non-profit organizations, the Malaria Vaccine Initiative (MVI) and the Infectious Disease Research Institute (IDRI). Other recent developments that could increase Indian research capacity include the launch of Emory’s Joint Vaccine Center with the International Center for Genetic Engineering and Biotechnology (ICGEB) in New Delhi, and the Hilleman Laboratories partnership between Merck and the Wellcome Trust, a US$145million not-for-profit initiative that will support 60 R&D staff.

Bring out the big guns

Immunology is often discussed in military-related metaphors, and this extends to the new technologies now available to vaccine researchers. “Each scientific advance means a new weapon in the armament,” says IAVI’s Hassell. Since recombinant DNA vaccines emerged in the early 1980s, vaccine technology has diversified from culturing and attenuating whole microorganisms. One recent development is the boom in cheaper, faster DNA sequencing. “Genome-wide sequencing is a common tool now,” says CIIL’s Locht, explaining that the technology enables researchers to examine the effects of a vaccine at the genetic level.

MedImmune headquarters in Gaithersburg, Maryland in the United States; the company is a leader in respiratory vaccines. Credit: LIGHTHOUSE PHOTOGRAPHY/MEDIMMUNE

As well as assessing efficacy, DNA sequencing can also be used to check vaccines for contamination with errant genetic material. Other technologies that have become integral to vaccine research include biochemical techniques such as protein purification and characterization, and improved assaying and imaging tools such as mass spectrometry, nuclear magnetic resonance (NMR) imaging and fluorescent tagging. “Vaccinology is very integrative,” says Locht. Delivery technologies are another active area of research; Locht and his collaborators, for example, are developing a new pertussis (whooping cough) vaccine based on a single nasal dose of a live attenuated bacterium.

Despite recent advances, there is still significant potential for breakthroughs. “Immunology is a field in the dark ages,” says MedImmune’s Projan, emphasizing the need for improved in vitro and in vivo models for testing vaccines. Despite common perceptions, there isn’t enough pharmacology expertise across the industry, he says.

There is a renewed focus on basic science to better understand the mechanism of vaccines and to develop new candidates, and an increasing interest in therapeutic vaccines for conditions such as chronic viral infections and cancer. “The vaccine field is going to enlarge substantially beyond the traditional preventive vaccine,” says Ahmed of EVC. Bioinformatics and systems biology are also crucial aspects of future vaccine research.

At MedImmune, a leader in vaccines for respiratory diseases, valued skills include initiative and working under multiple managers. “It is increasingly complicated to discover, develop and commercialise [a new vaccine],” says Projan. “We can’t rely on staid, formal, hierarchical reporting relationships.”

And it is not just in R&D that jobs will expand. “You’re also going to see opportunities in non-technical areas such as project management, regulatory affairs, clinical development and so forth,” says Carpick.

Two years into Bill Gates’s decade of vaccines, there is much optimism and potential for stimulating opportunities for scientists with the right skills. “It’s one of the most exciting areas of science right now,” says Ahmed.