A basic tenet of vaccinology is that the prohpylactic vaccine induces immunity. Thus, an immune state must be possible. In the case of HBV, the immune state is indicated by the presence of antibodies against HBsAg (the hepatitis B surface antigen), also known as the anti-HBsAg IgG. This neutralizing antibody is also known as the correlate of immunity. Thus, any effective vaccine for HBV must the production of anti-HBsAg IgG in the host. See our Virus Page for more information.


Vaccines against HBV were first made from the serum of people who had been HBV infected and subsequently cleared the infection. Because these individuals naturally produced anti-HBsAg IgG and then cleared the infection, they were immune to reinfection with HBV. The serum from these individuals was taken and purified antibody was passively administered to others in order to induce immunity. Although this strategy works in a theoretical manner, there are complications including supply shortage and host rejection of the foreign antibody. 19, 23.


In the early 1980's, researchers discovered a new way to produce this antibody utilizing recombinant DNA technology. In an infected individual, HBsAg is present in two forms: as a protein on the surface of the 42 nm virion (also called the Dane particle) and as a secreted 22 nm particle that is a hollow sphere of surface antigen. Using the yeast Saccharomyces cervisiae, researchers created a vector which contained the coding sequences for this surface antigen of HBV, HBsAg. The key to this success was that the yeast assembled this 22 nm protein in the same way that excess surface antigen assembles and is secreted in humans. Therefore, the artificial surface antigen resembled the naturally occuring particle. 24.

 

image taken from Valenzuela, et al. Nature 1982 24.

EM at 25,000 x and 250,000 x of the 22 nm HBsAg particles produced by yeast cells.

 

data taken from Valenzuela, et al. Nature 1982. 24. image created by Neil Wimmer

 

Schmatic of the vector constructed by Valenzuela et al. in 1982 that contained the S portion of the HBsAg gene.

 

One reason finding an alternate vector for expression of these surface antigen genes was so important in creating an effective vaccine was that this 22-nm particle could be administered safely to humans. Because the 22-nm particle contains the surface structure of HBV but does not contain the DNA of the actual virus, humans exposed to this product could produce their own anti-HBsAg IgG without any risk of being infected by HBV itself. Because the host was now producing her own antibody rather than passively receiving it from another individual, immunity was more likely to be long-lived and more effective. With the advent of recombinant DNA technology and the creation of the yeast vector, it was possible to create the first safe, effective recombinant vaccine for human use. 9, 13. See our The Vaccine Future Page and Vaccine Issues Page for more on this topic.


Shortly after the yeast vector was created, researchers from France created a similar particle that could induce the correlate of immunity. This time, the recombinant plasmid was transfected into Chinese hamster ovary (CHO) cells. Also, this plasmid was different than the recombinant yeast plasmid because it included an extra piece of the genome (See Virus Page). While the yeast plasmid included only the S gene of HBV, the CHO clones used the S gene plus the pre-S2 portion of the genome, creating a vector that began one start codon upstream in the genome. In this case as well, the 22-nm particle containing the immunogenic HBsAg was produced by the artificial system. The researchers who created this vaccine tested its efficacy against the efficacy of HbsAg molecules purified from human systems, and found the efficacies to be identical. This lent support to the idea that these artificial particles are as immunogenic as the naturally produced ones. 20.

 

image taken from Michel et al. PNAS 1984. 20.

EM of HBsAg particles produced in Chinese Hampster Ovary cells (CHO). These particles include the peptide coded for by the pre-S2 portion of the genome.

The two major producers of HBV vaccine containing the HBsAg that are available in the United States are Merck and SmithKline Beecham. In other parts of the world, there are several companies producing recombinant vaccines (such as Pasteur Merieux Connaught in France) as well as a few that are still selling plasma derived vaccinations. The two vaccines produced by Merck contain only the S portion of the genome, whereas the vaccine produced in France, GENHEVAC B, contains the pre-S2 peptide as well. Yeast-based vaccines are most widely used. Today, the standard vaccine consists of three doses given intramuscularly in the deltoid muscles of children, adolescents, and adults, and in the anterolateral thigh muscle of children under two.

 Manufacturer

Brand Name

Type of Vaccine
 Centro de Ingeniera Genetica Y Biolotecnologia Enivac-HB Recombinant DNA
Chiel Jedang Hepaccine-B Plasma derived
Korea Green Cross Hepavax B Plasma derived
Korea Green Cross Hepavax-Gene Recombinant DNA
LG Chemical Euvax B Recombinant DNA
Merck Sharpe and Dohme Recombivax H-B Recombinant DNA
Merck Sharpe and Dohme Comvax Combined Hib and recombinant DNA
Pasteur Merieux Connaught Genhevac B Recombinant DNA (mammalian cell)
SmithKilne Beecham Engerix-B Recombinant DNA
SmithKilne Beecham  Twinrix Combined hepatitis A and B (recombinant)
SmithKilne Beecham Tritanrix-HB Combined DTP and recombinant
Swiss Serum and Vaccines Institute Heprecombe Recombinant DNA (mammalian cell)

Information from 19, 23, www.sb.com, www.merck.com, www.aventispasteur.com

 

The production of this vaccine has been a major force in reducing the burden of disease due to HBV everywhere that it has been used (see Epidemiology Page). All of the efficacy studies show that 95% of subjects who receive all three doses of the vaccine are protected against HBV infection, providing evidence of the ability of this vaccine to combat the prevalence of HBV. One study in particular, conducted in Afragola, southern Italy, revealed the effects of a vaccination program in a hyperendemic area. Before this pilot project began, the incidence of HBV in the population was found to be 63/100,000, and HBV was found to be involved in 48.1% of chronic liver problems in 1978. Then, in 1983, the vaccination program began with immunization of all new born babies, and expanded in 1991 to include the vaccination of all 12 year old children. In 1997, the population was reassessed, and the incidence of HBV had dropped from 63/100,000 to 3/100,000, and, the HBsAg carrier population dropped from 13.4% of the general population in 1978 to 3.7% in 1997. Furthermore, the involvement of HBV in chronic liver pathology decreased to 18.2% of cases in 1997, a drop of 29.9% from 1978. Thus, it is clear that when people receive the HBV vaccine, the burden of disease decreases significantly over time. 9.

 Data from one of many efficacy trials...

image taken from Da Villa et al. Res Virol. 1998. 9.

Given that the HBV vaccine makes such a difference in the burden of disease, who should receive this vaccine? The answer to this question is not as straightforward as it may seem. The recommendations have changed over time. For example, in 1994, the Advisory Committee on Immunization Practices (ACIP) added two categories to the growing list of those who should be vaccinated. These were: 1. All unvaccinated children under 11 years of age who are Pacific Islanders or who live with generation immigrants from countries where HBV is of high or moderate endemicity; and 2. All children of 11 or 12 years of age who had not been previously immunized. Before this change in the recommendation, the standard practice was to integrate the HBV immunization into the new born vaccination schedule due to the prevalence of HBV in other populations, however, the list of those who should be vaccinated continued to grow. As of 1999, the recommendations in the United States are as follows:

WHO, the World Health Organization, recommends that the HBV vaccine should be incorporated into national vaccine programs everywhere. In order to this, however, full governmental support is necessary. Unfortunately, political support in many nations has been lacking, and there are many countries where the vaccine is not yet standard. 26, www.who.org.

 

image taken from World Health Organization. www.who.org

World Health Organization data from 1996 indicates that many of the countries in endemic areas do not have either an ongoing or proposed program for HBV vaccination. See Vaccine Issues for a more thorough discussion of universal vaccination.

 

 


 Epidemiology

Virus

 Pathology and Treatment

 The Vaccine

The Vaccine Future

 Vaccine Issues

 References

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