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PERSPECTIVEWhy Certain Vaccines Have Been Delayed Or Not Developed At All
Vaccine development is a long process, with the time from early research to licensure steadily increasing. At one time the process took about ten years; now it takes closer to fifteen to twenty years. The process begins with investigators in universities or biotech firms who have an idea. However, to take things further, there must be a vaccine manufacturer, a regulatory authority ready to give permission for the use of the vaccine, and public health authorities that will recommend and foster vaccination.
If we think about public health needs, the fact is that the list of diseases for which we do not have vaccines far exceeds the list of those for which a licensed vaccine is available.1 Moreover, there are diseases for which preliminary studies suggest that a vaccine is feasible, but there is no concerted effort to develop one. Why is this the case? Certainly part of the reason is the discouragement of the industry that develops vaccines, as explained by Paul Offit in this volume of Health Affairs.2
There are too few major manufacturers of vaccines. In terms of sales, five manufacturers dominate the market, which is estimated to be about $8 billion. As research and development (R&D) budgets relate directly to profits, industry R&D is concentrated in those five companies. My estimate of the total worldwide R&D budget for the industry is less than a billion euro each year. Competition with drug projects. The great majority of vaccine manufacturers are owned by pharmaceutical companies, which is a deleterious situation because vaccine projects must compete with drug projects for funding, and drugs are more likely to yield a high return on investment, as Offit explains. It is estimated that each vaccine costs $300–$800 million to develop, but only a handful have been blockbusters, which dampens the enthusiasm of pharmaceutical executives. The absorption of vaccine producers by pharmaceutical companies has been inexorable, and it is argued that this arrangement provides greater capital and synergy between pharmaceuticals and vaccines. However, it might be preferable if vaccine companies were the subject of public offerings on stock exchanges. Then individual investors could support vaccine enterprises, knowing that they would not make huge profits but that the industry would produce steady returns and would be unlikely to go bankrupt. For that matter, governments could also invest in companies that provide the vaccines for their population, and special bond issues could be issued for projects that reach the costly Phase III stage, at which point there is a good chance of a licensable vaccine. Bottlenecks for new vaccines. The concentration of vaccine development in few hands makes for bottlenecks. Academic investigators all want their idea to be tested in humans, but although it is true that there are a number of biotech firms besides large manufacturers that can make Phase I lots under current Good Manufacturing Practices (cGMP), it is also true that the talent to develop and scale up experimental vaccines is rare and tends to be concentrated in a few organizations. Thus, a triage occurs, in which a few organizations decide which experimental vaccines will be tested for proof of principle. The decision is based on many factors, the first of which is the market—or, in other words, how many doses of the vaccine could be sold if the project produced a licensed vaccine. This attitude is not unreasonable, because it is unproductive to make a vaccine that will not be used. Imprecise marketing estimates. Marketing departments often come up with precise figures on market size and related parameters. The basis for these precise figures is often imprecise estimates, but when numbers are multiplied together, they somehow acquire a degree of certitude that gives false comfort. The fact that they are guesses is often lost in the PowerPoint charts. A retrospective analysis of the correctness of marketing recommendations to see if they are better than chance is long overdue. Among the factors that enter into decisions about vaccine development, aside from market and public health interests, technical feasibility is certainly key. Manufacturers are not in the business of basic research, and if there is no evident feasibility for the scaling up and production of a particular vaccine coming from academia or a biotech firm, it will be quickly abandoned. That is understandable, but not infrequently a vaccine will be abandoned prematurely when a technical problem in the development arises, even if that problem could be circumvented. Intellectual property problems. Another important factor is intellectual property. This remains a quagmire, into which companies hate to enter.3 Patents are an incentive to innovation and encourage investors to provide funds for product development. However, they may also block developers from entering a particular domain and block collaboration between entities that both hold intellectual property. The recent controversy about the patenting of the human genome illustrates the problem, which extends to patenting of the sequences of microbes. The latter potentially means that whole organisms are off-limits to more than one company. The formation of consortia is one way to get around the intellectual property problem, and this has been recommended for AIDS vaccine development, but it is not yet a reality. Taking into account all of these factors that play a role in industry decisions and the fact that there are only a few organizations capable of final development, relatively few vaccines progress to the late stages of clinical development.
The primary function of regulatory authorities is to guarantee safety and efficacy of licensed products, and it is therefore not surprising that other considerations may be neglected, so that regulation may be harmful to public health, without intending to be so. Fujian flu vaccine. Early in 2003 it was apparent that the circulating influenza A/H3N2 strain was being replaced by a new strain, emanating from Fujian, China. However, at the time the choice of strains for the 2003–04 season had to be made, the only isolates of Fujian available had been cultivated in laboratory stocks of Maden-Darby canine kidney (MDCK) cells. Although those cells have been proposed as substrates for flu vaccines, they are not yet accepted by most regulatory authorities, and the cells used for isolation had not been validated.4 Because of a concern that the isolates might be contaminated by a hypothetical agent in the MDCK cells, a regulatory decision was made to keep the old strain instead of using the MDCK cell–passaged virus as seed. Of course, influenza seed viruses are routinely isolated in eggs, and the inocula come from patients who may carry unknown viruses in their throats. Nevertheless, because there was at the time no primary isolate in eggs of a Fujian-like strain, the regulatory authorities recommended the retention of the prior H3N2 virus.5 This decision resulted in a 2003–04 vaccine that gave only 38–52 percent efficacy against all strains and probably less than strain.6 The balance between a theoretical risk and mortality attributable to influenza was resolved in favor of the theoretical risk. Intranasal flu vaccine. Another example is the history of intranasal influenza vaccine (known as Flu-Mist), now licensed in the United States for people ages five to fifty. The exclusion of children younger than age five meant that the vaccine could not be given to infants ages 6–23 months, the age group that has just received a universal recommendation for vaccination because of their high influenza morbidity and even mortality. Moreover, this was an age group in which high efficacy had been demonstrated in a detailed Phase III trial.7 The exclusion of "under-fives" was based on reports of asthmatic illness in children who had been vaccinated. Analysis of the data, however, suggests that this may have been an artifact of coding, because when total wheezing illness was analyzed, there was no difference between those who had been given the intranasal flu vaccine and those who had been given a placebo. Moreover, the wheezing episodes were not serious and did not require hospitalization.8 When one takes into account the high efficacy of intranasal flu vaccine in young children, it appears that protection against a serious infection and the possible epidemiologic effect of preventing disease in children were given second place to concern about a mild and treatable putative adverse reaction.
The case of Lyme disease. In this jeremiad, the public health establishment does not escape whipping. Just how helpful is it to vaccine development? Take the example of the Lyme disease vaccine based on the recombinant production of the OspA membrane antigen of Borrelia burgdorferii. Two companies expended considerable human and financial resources to develop a vaccine for a disease that causes 15,000–20,000 cases per year, mainly in the northeastern part of the United States.9 However, the reaction of the U.S. Centers for Disease Control and Prevention (CDC) and its Advisory Committee on Immunization Practices (ACIP) was to damn the vaccine with faint praise. Emphasis was put instead on wearing protective clothing and using tick repellents, despite the paucity of controlled data showing that those measures work and even fewer data showing that people actually use them.10 The enthusiasm of physicians for the vaccine was therefore tepid, leading to few vaccinations. Admittedly, false safety issues also arose, but in the end, lack of demand caused by weak public health recommendations led the manufacturer to withdraw the vaccine. Improved Lyme vaccines will not be proposed for license unless authorities take a more positive attitude. Vaccine priorities. Public health authorities need to indicate which vaccines would be used if they were developed. The recent Institute of Medicine (IOM) report on priorities for vaccines is a signal example of what can be done, but to my knowledge it has never been discussed by the ACIP, nor has the ACIP indicated which of the priorities given by the IOM it agrees with.11 Vaccination during pregnancy. There is also the situation regarding vaccination during pregnancy. Many vaccinologists have recommended that consideration be given to vaccination of pregnant women, to transmit protection to their infants. Group B streptococcus, pneumococcus, respiratory syncytial virus (RSV), and other infections have been the subject of such recommendations. However, manufacturers are afraid of vaccinating during pregnancy, given the 2–3 percent prevalence of congenital abnormalities and the litigiousness of U.S. society. Clearly, the only way out of this dilemma is either to have legislation that indemnifies manufacturers against nonnegligent actions or to include maternal vaccination in the compensation system. Nevertheless, politicians have not heard from the public health community to obtain those protections. Developing countries. Authorities in developing countries are not doing any better. The Rotashield vaccine proved to be highly effective at preventing serious rotavirus disease in both the United States and Latin America but was withdrawn by the manufacturer after cases of intussusception were associated with the vaccine in the United States at a rate of about one per 10,000 infants who were vaccinated.12 Because dehydration attributable to rotavirus still kills about 500,000 infants annually, the World Health Organization (WHO) held a meeting in Geneva at which representatives of developing countries were offered the vaccine by the manufacturer. The WHO urged acceptance, but the offer was met with silence. No country was willing to place public health above possible criticism for using a vaccine rejected by the United States. This was not exactly a profile in courage. In conclusion, public health needs for vaccines are sometimes impeded by the very people and organizations that have most reason to satisfy those needs: manufacturers, regulators, and public health authorities.
Stanley Plotkin (Stanley.Plotkin{at}sanofipasteur.com) is emeritus professor of pediatrics at the University of Pennsylvania. The author is executive adviser to the chief executive officer of Sanofi Pasteur, an international vaccine manufacturer, but this paper reflects his personal opinions only.
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