A broad survey of industry indicates that the Chemistry. Manufacturing and Controls (CMC) development for a vaccine exceeds 50M USD and consumes more than 80 person-years in human resources. Despite the difficulty of quantifying costs, one risk-adjusted estimate of R&D costs is 135-350 M USD. In addition to that, André suggested in another report that the total costs of vaccine development can range from 200 to 500 M USD and can take more than 15 years (André, 2002). From all these reports, in order to reduce the development time and especially the cost inherent in research and development, most manufacturers from developing countries may choose to obtain technology from major multinational manufacturer. Consequently, this strategy enables lower prices for vaccines, which is appealing to public health authorities in those countries (Plotkins et. al, 2017).
Genuinely, vaccine production involves high investment costs. From the timeline in yellow fever vaccine production, there were various research and development as well quality control are involved. However, vaccine production costs per units can be reduced significantly through gains in productivity and through economic scale. As vaccine production costs have a significant fixed cost component, the cost of production per dose decreases with increasing batch size. In this case, the yellow fever vaccines are relatively low because of the fixed cost of production have been covered long ago and due to the learning curve and economies scale. In addition, the production of live attenuated vaccine is relatively cheap and simple to produce as the requirement of adjuvants are not necessary. Hence, the cost for measles vaccine is approximately $75 per shot.
Even though the live attenuated vaccine able to provide longer-lasting immunity and are an economical and simple means for efficacy vaccine production, but development of live-attenuated virus vaccine for human pathogens can encounter safety concerns due to under-attenuation of the virus or even a reversion to its pathogenicity. This is because it is nature for living organisms to change or mutate. However, the reversion to pathogenicity has never been observed with yellow fever vaccine until today. Typically, the stabilizer substances are added to bulk vaccine. The stabilizer did not affect the immunogenicity and yet stabilized the vaccine. As a result, the vaccine can give a consistently good performance (WHO, 2017).
In another example such as in efforts to develop live attenuated HIV vaccines, researchers have investigated live-attenuated simian immunodeficiency virus (SIV) vaccines as proof of principle and found strong levels of protection in non-human primate. Unfortunately, live-attenuated SIV vaccines can also cause AIDS in vaccinated monkey due to reversion to pathogenic form (Barrett & Stanberry, 2009). In the case of the Sabin Polio vaccine, about 10 vaccine-related cases of paralytic polio occurred every year in United States due to reversion to virus virulence (Strauss & Strauss, 2007).
On the other hand, inactivated vaccines are totally different from the live-attenuated vaccines as the diseases causing pathogen are killed with chemical or physical (heat or radiation) processes by destroying the pathogen’s ability to replicate but is kept intact for the immune response to recognize it. As a result, these killed organisms cannot cause any diseases. This indicated that this vaccine may not always induce immune response and if there’s any induced response, it may not long live. Hence, several doses of inactivated vaccines are required to evoke sufficient immune response. Hepatitis A vaccine is an example of formaldehyde-inactivated vaccine which is used in most countries. Hepatitis A is an acute infection of the liver due to hepatitis A virus which commonly transmitted by the fecal-oral route via contaminated food or drinking water (HHS, 2017).
Globally, hepatitis A virus (HAV) is one of the most frequent causes of foodborne infection. The HAV is a member of the family Picornaviride with an icosahedral capsid that is highly resistant to environmental conditions and exists as a single serotype. The WHO estimates that each year there are about 1.4 million cases of hepatitis A infection worldwide. Until up-to-date September 2017, according to the Australia Health government, there are only about 90 people got infected with hepatitis A and the number of infection had been gradually decrease since the late 1990s due to the hepatitis A vaccine. Therefore, hepatitis A vaccine is extremely effective in preventing infection. Immunisation against hepatitis A can be achieved using a single-disease vaccine (WHO, 2017).
Normally, hepatitis A vaccination is recommended for all children aged 12 months or older, adults in most of the country especially developing countries with poor hygiene standard, adult with high risk and for travellers. This vaccine prepares body to fight off the hepatitis A virus by given by intramuscular injection in two shots with six months apart. The first shot will be given up to 12 months of protection against hepatitis A. After 6 to 12 months, a booster injection for hepatitis A will give up to 10 years of protection depending on the type of vaccine. For instance, Avaxim can provide 10 years of protection following booster whereas Exapal provide 20 years of protection. Besides that, the length of protection provided is different in adults and children. According to a recent review by an expert panel, the experts concluded that protection levels of antibody to hepatitis A virus could be present for at least 25 years in adult and at least 14-20 years in children (Australian Government Department of Health, 2017; CDC, 2017).
In 1979, the path of for the vaccine development was open when Hilleman and Phil Provost could successfully grow HAV in cell culture. Hilleman, Provost and colleagues developed the first inactivated HAV in 1986 but was not suitable for use in human. After years of studies ad research, finally the formaldehyde-inactivated, whole-virion HAV vaccines grown in human fibroblast were developed and the first hepatitis A vaccines were first licensed for use in 1992 (Plotkin et al., 2008). Currently, there are two types vaccine that are available; the monovalent vaccine and combined vaccine.
According to Albert Bosch from University of Barcelona, the HAV has several highly specific characteristics and it is difficult to process in the laboratory setting due to the low replication rate. Hence, the process of obtaining a vaccine antigen is slow and very expensive. In 2015, AVAXIM, hepatitis A monovalent vaccine inactivated was approved and widely distributed in Canada. The active ingredient is a purified and formaldehyde-inactivated HAV obtained from GBM strain, cultured on MRC-5 human diploid cells and HAV is adsorbed onto aluminium hydroxide.
Hepatitis A vaccines are highly immunogenic in both children and adults with virtually universal seroconversion 4 weeks after vaccination. In the research for the hepatitis A vaccine, two randomised clinical trials conducted in 1990s showed that the vaccines have a very high protective efficacy approaching 100%. In the first study conducted by Werzberger and colleagues, both three-dose regimens and two-dose regimens of the inactivated vaccine have been evaluated in healthy adults and children. The vaccine has been shown to be tolerated and immunogenic and a single dose induces high titres of antibodies within two to four weeks. Geometric-mean antibody levels increases about 10-fold with each addition injection. IgM antibody to hepatitis A can be detected shortly after the first or second injection (Werzberger et al., 1992). In another study for safety and efficacy, Innis and colleagues concluded that inactivated hepatitis A vaccine is safe when administered in two doses. (Innis et al., 1994)
In addition, the efficacy of vaccine has been determined by the comparison of the antibody titres produced by AVAXIM with that of a control Hepatitis A vaccine that confer protective efficacy in a controlled trial in healthy individual from Thailand. In the first pivotal study, AVAXIM immunogenicity was assessed at 8 weeks after the primary injection with 99.3% of subjects achieving seropositive titres. The geometric mean titre (GMT) was 138.4 mLU/mL. The seroconversion rate 4 weeks post the last dose was 100% with GMT of 4,289.6 mLU/mL. In the second pivotal study, 100% of subjects were seropositive 8 weeks after the primary injection with the GMT being 114 mLU/mL. Four weeks after the booster injection the GMT had risen to 3,557 mLU/mL. The data of the study is shown in Table 1 (Sanofi, 2012).
(Sanofi, 2012)
For the production cost, the inactivated vaccines are relative high as they involved in more complex manufacture. Large expenses are required in preparing the large amounts of material required, the necessity for multiple inoculation in the case for most such vaccine and the failure to induce a full range of immune responses. Large amount of materials must be injected to induce an adequate immune response due to no virus replication occur. Furthermore, lack of virus replication means that an inflammatory response that is required for an efficient immune response must be obtained by using adjuvants that are incorporated into vaccine (Strauss & Strauss, 2007; Sanofi Pasteur SA, 2015). As a result, the cost for the hepatitis A vaccine is approximately $120 for two doses.
In the case for AVAXIM, the fact that the viruses are inactivated or no live virus was ever present means that no virus infection occurs with its potential for disease. Thus, this inactivated vaccine is more stable and safer as dead pathogens cannot mutate back to their disease-causing state (The College of Physician of Philadehia, 2017). Until today, there is no any cases of virus reversion that can be found in any inactivated vaccine. The possibility for inactivated vaccines for reversion are really low too.
From the two types of vaccine that had been discussed, it can be concluded that the live attenuated vaccine can elicit a strong and protective immune response with a low risk of disease from the vaccine itself as live pathogens are introduces into the body. This is an excellent stimulation for the immune response. Due to this characteristic, live-attenuated vaccines can result in lifelong immunity with just one as it induces full activation of both humoral and cellular immunity and to the fact that viral antigens are present during the entire course of infection. Moreover, this type of vaccines does not require any adjuvants and the cost of production is less expensive with simpler manufacture (Zucker, 2012).
However, this type of vaccine does have some of risk in which individual with weakened immune response are not suitable to receive this vaccine. This is because there’s a risk for the pathogen could get stronger and cause disease in an individual with weaken immune response because live-attenuated vaccines consist of live pathogen. These vaccines can also be interfered by other infection and there is possibility of being excreted when introduced into the body (Zucker, 2012).
As compared to the live-attenuated vaccine, in inactivated vaccines, pathogens that are killed by physical or chemical means are introduced into the body. Even though the pathogen is dead, the immune system still can be induced. The main advantage of inactivated vaccines is safer, without risk of the pathogen mutating back into its disease-causing form. This proved that inactivated vaccines have a greater safety and stability as they are less susceptibility to changes in temperature, humidity and light which can result.
Since the inactivated pathogen can’t replicate, they tend to provide shorter length of protection. As a result, several doses and boosters of vaccine with adjuvants are required to create long-term immunity. Inactivated vaccines can also increase the risk of allergic reactions due to large amounts of antigen involved. In certain condition, inactivated vaccine is inefficient because some of the antibodies will be produced against parts of the pathogen that play no role in causing diseases. And finally, these vaccines do not give rise to cytotxic T cells which can be important for stopping infection by intracellular pathogens (Baxter, 2007). As a conclusion, both live-attenuated and inactivated vaccine had their advantages and disadvantages.