Developing Vaccines – Complexities, Steps and Capabilities

Whatever the technology used, the process of development of a vaccine is very complex and long. The average time for the development of a product is estimated to be between 10 and 15 years but it can take longer (Homma et al., 2003). A vaccine against HIV, for example, has been pursued unsuccessfully for more than 20 years.¹⁴⁹ As time has passed, technical requirements to license a human vaccine have become stricter, and new pre-clinical and pre-clinical trials have been required in order to make the products safer. The

145 The boom of Biotech firms has its origins in the US Bayh-Dole Act in 1980, which allowed universities and small enterprises to patent discoveries and license them to the large pharmaceutical firms even when the research had been financed by the public funds of NIH (Mazzucato and Dosi, 2006).

146 The case of Biotechs is also approached in Chapter 6, Sub-section 6.2.2 (pg. 125-128).

147 Food and Drug Administration (FDA) in the USA, European Medicines Agency (EMEA) in Europe and Agência Nacional de Vigilância Sanitária (ANVISA) in Brazil are examples of national regulatory authorities.

148 These and other actors are also approached in the section about Government and Institutions in the next chapter on pg. 151-161.

149 The Jordan Report 2000 (NIH/NIAID, 2000:85) reports HIV vaccine studies funded by NIAID since 1987 involving a great range of actors.

investments required became huge and returns uncertain, which makes the business too risky (Hinman et al., 2006). Estimations suggest that the cost of vaccine development ranges between US$300-800 million (Plotkin, 2005c),¹⁵⁰ and few manufacturers have managed to accomplish all the stages of a vaccine’s development (Orenstein et al., 2007). In fact, most projects fail. Table 5.6 below outlines the status of vaccine R&D in 2006 and the probabilities of launching in each of the R&D phases.

Table 5.6: Vaccine R&D Projects – Status and Market Entrance Probabilities Basic

Research Pre-clinical Clinical Trials I

Clinical Trials II

Clinical

Trials III Registration Status of Vaccine R&D in 2006 – 448 Vaccine Projects / 115 Target Agents⁽¹⁾

84 180 68 63 53 -

Market Entrance Probability⁽²⁾ - %

- 22 39 54 68 96

Own elaboration

(1) Source: NIH/NIAID (2007:Appendix A). Data refers to publicly available information only. HIV projects not included.

(2) Source: Struck (1996).

The complexities of vaccine development may be illustrated in other ways. Compared with drugs, there is no bioequivalence procedure for vaccines, which means that there are no “generic” vaccines and therefore any new or improved vaccine should go through at least limited clinical trials (Milstien et al., 2007). Moreover, as briefly approached in footnote 123 of Sub-section 5.2.1 (pg. 95), the same disease may be caused by different microorganisms due to specific population characteristics (WHO, 2002b:xi), which makes the development of potential globalized vaccines technologically challenging (Milstien and Candries, 2002).

According to Homma et al (2003), the typical process of development of a vaccine comprises seven main steps. However, these authors emphasize that this process is far from being linear since the need to return to previous steps is not uncommon.

Additionally, as pointed out by Bomtempo & Baetas (2005), the frontiers of these steps are flexible since some activities are superposed. The basic steps are summarized as

150 The cost of the development of the live attenuated influenza vaccine may have exceeded US$ 1 billion (Orenstein et al., 2007).

follows, based on Homma et al. (2003) and Bomtempo & Baetas (2005), and represented in Figure 5.1.

Step 1 – Discovery/Invention: in this first step basic research is performed in very well equipped laboratories and by very skilled and multidisciplinary researchers and technicians to set up a scientific understanding of the etiology of the disease, the interactions between human being and pathogen, and the immune response of the human being. Researches on new adjuvants and molecules are also performed within this step. Infectology, biochemistry, epidemiology, immunology and microbiology are amongst the main capabilities required. Molecular biology, genetic engineering and studies on the genome are increasingly used technologies in this phase.

Step 2 – Pre-development studies: this step includes studies on the identification and analyses of the antigen(s), on the modification of its virulence and on the determination of its stability and immunogenicity. In addition, material is specified and several studies are repeatedly performed in the same conditions and parameters in order to standardize the methodology of production, to obtain the biological and physic-chemical characterization, to test the reproducibility, to establish the parameters of scaling-up and, in short, to show its technical feasibility to become a product. Similar capabilities are required in this step.

Step 3 – Candidate Vaccine and Pre-Clinical Trials: in this step a candidate vaccine is designed, developed and produced for the pre-clinical studies. This includes adjuvants selection, vaccine presentation (e.g. liquid or freeze-dried, intramuscular or oral) and formulation parameters. The pre-clinical trials consist of evaluating the inocuity, reactogenicity, toxicity and immunogenicity of the potential vaccine to determine the level of risk of inoculating it in humans. The tests are performed in selected in vivo animals especially grown for use in research, and in laboratories that comply with Good Laboratory Practices (GLP). Veterinarians are amongst the professionals performing these activities.

Step 4 – Vaccine for Clinical Trials: since an acceptable level of risk in administering the potential vaccine in humans is demonstrated in the pre-clinical trials phase, experimental lots of the vaccine are produced to be tested in clinical trials. The lots are

produced in pilot plants that simulate the same conditions of production facilities. ¹⁵¹ The scale-up process encompasses an industrial dimension and Good Manufacturing Practices (GMP) are required. The commercial feasibility is determined in this phase.

New capabilities are incorporated for the development of these activities, amongst them engineering (chemistry, biochemistry, production, economic), marketing and regulation.

In this phase the seed lot is prepared to assure the reproducibility of subsequent lots. All the parameters defined in this phase cannot be modified after the clinical trials otherwise new trials will be required.

Step 5 – Clinical Trials: these trials are very complex and sensitive since they are carried out on human beings. With the introduction of new regulatory and safety standards, clinical trials have become the major expense in the process of development (Milstien and Candries, 2002) and may take several years to be carried out. They are divided into three distinct phases:

 Phase I: the safety of the vaccine is tested in a small number of adults and healthy volunteers;

 Phase II: the immunogenicity of the product is tested in an amplified population.

In this phase the real product is compared to a placebo and the adverse effects studies are extended;

 Phase III: the efficacy of the vaccine is the main purpose of the tests in this phase, which are carried out on a larger population preferably from endemic areas. The immunogenicity and adverse effects studies are complemented in this phase.

When performing clinical trials for an improved vaccine, the old one should be used as a reference during the tests: Good Clinical Practices (GCP) should be observed during these trials (Milstien, 2005). The capabilities required for performing clinical trials are somewhat different, as shown by Bomtempo & Baetas (2005), and include ethical procedures. Moreover, they are restricted to a limited number of research centres (WHO, 2002b). There is a trend, therefore, to outsource the clinical trials to specialized organizations also called Contract Research Organizations (CROs) (Milstien and Candries, 2002).

151 The vaccine for Clinical Trials Phase III is produced in the production facilities (interview 11).

Step 6 – Registration – Detailed documentation about the development, production and quality control methodology, and pre-clinical and clinical trials results, must be submitted to the regulatory authority in order to obtain the license to market the product.

Once licensed the product cannot be modified in any of its characteristics otherwise new studies must be carried out and the results re-submitted to the regulatory authority. For this step, deep knowledge about the regulation is required.

Step 7 – Post-Marketing Trials: also called Clinical Trials Phase IV, this step is performed after the commercialization of the licensed vaccines and consists of testing a large population of vaccinated people to monitor the results of the vaccination with regard to both any adverse effects – rare or delayed adverse reactions not detected in smaller trials – and to the global impact over the disease. The tetravalent rhesus-based recombinant rotavirus vaccine, for example, was withdrawn from the market after some adverse risks were identified in the post-licensure tests (Hinman et al., 2006; Milstien and Candries, 2002).

Own elaboration. Source: Homma et al. (2003), Leal (2004), Moreira (2005) and Plotkin (2005c)

Figure 5.1: Developing a Vaccine: Key Steps and Aspects

Pre-development Studies