The Cornerstone of Vaccination

Experts cite advantages of six-in-one formulation

In the world's fight against infectious diseases, no medical breakthrough has had the greatest impact on health than the development of vaccines. Widespread immunization has enabled humanity not only to drastically cut down mortality and morbidity but to wipe out some diseases in many parts of the world, if not yet the whole world. Smallpox today is virtually unheard of, one of the greatest milestones in the medical field. In October 2000, the World Health Organization declared the Western Pacific Region--which includes the Philippines-polio-free. Poliomyelitis and measles are now priority targets for global eradication.

    The success notwithstanding, the search for vaccines that are more effective, safer, and easier to administer goes on. Efforts have also been directed at combining vaccines in one preparation to reduce the frequency and number of injections a child has to go through, and simplify and speed up administration.

    One of the latest in combo-vaccines is Hexavac, the result of a decade of research by Aventis Pasteur and Merck Sharp & Dohme.

    On October 23, 2000, Hexavac was licensed in Europe, where it is now widely used. It was introduced in the Philippines early this year, making the Philippines the first Asian country to use the vaccine.

    At its launch, two prominent specialists in the field of immunology and infectious diseases traced the evolution of vaccines and the history of Hexavac and presented studies to back up the six-in-one vaccine's efficacy and safety.

    Dr. May Book-Montellano, trustee of the Philippine Society for Microbiology and Infectious Diseases and assistant treasurer of the Philippine Pediatric Society, presented some challenges in childhood vaccination. Dr. Luc Hessel, executive medical director of Aventis Pasteur MSD, outlined the Hexavac research and development process and presented its use.

From Pertussis to Hexavac

    Combination vaccines are not new, although Hexavac is the first to contain all six antigens fully liquid in one easy-to-administer syringe.

    Providing the background for each of the six antigens contained in Hexavac, Dr. Montellano recalled that the vaccine for pertussis, which was the first to be developed, was later combined with those for diphtheria and tetanus. She said it was so effective it became one of medicine's landmark achievements--drastically reducing the incidence of these diseases--along with the introduction of the polio vaccine.

    However, she noted that, as its use became more widespread, along came reports of adverse reactions that were later traced to the vaccines being whole cell. Thus, the acellular vaccines were later developed, which greatly improved their tolerability without sacrificing efficacy (Figure 1). Acellular pertussis vaccine, she said, reduced local and systemic adverse reactions by about two-thirds. On the other hand, their respective efficacy rates overlap: 85 to 95 percent for whole cell and 75 to 90 percent for acellular.

    Dr. Montellano said acellular pertussis vaccine is the preferred type in the United States, most of Europe, Australia, and Japan.

    Another major advancement in vaccine research was the development of the polio vaccine in 1954. Nearly five decades since then, massive polio immunizations have made many parts of the world polio-free. Still, Dr. Montellano said this is no cause to be complacent, as she distinguished between the use of oral polio vaccine (OPV) and inactivated polio vaccine (IPV).

    She noted that because OPV may mutate in the gastrointestinal tract, there is invariably going to be the occurrence of vaccine-associated paralytic poliomyelitis. And although the mutation is only 0.5 percent or one in 2.4 million OPV doses, it can add to cases of acute flaccid paralysis. Cases of circulating vaccine-derived paralytic polio have been reported in the Dominican Republic, Haiti, and Egypt.

    "As long as we utilize OPV we are going to see mutations," she said even as she noted the growing use of IPV, either alone or in combination with OPV. While not advocating a change in the country's immunization program and schedule from OPV to IPV, Dr. Montellano said the latest studies show that IPV is as immunogenic and efficacious as OPV, capable of achieving 100-percent seroconversion rate with just two doses. She stressed that at present, OPV is "the only tool that we can utilize to stop transmission of poliomyelitis--whether arising from the wild poliovirus or vaccine-derived."

    "But with IPV, we can really eventually remove the adverse event of vaccine-associated paralytic poliomyelitis and the circulating vaccine derived paralytic polio," she noted.

    The problem, she said, is how to incorporate the two without adding to the already complicated immunization schedule. And the answer, she said, lies in using a combination vaccine.

    Use of combination vaccines, she stressed, has a number of advantages. For the child, it means fewer injections, thus less distress. For parents, it means fewer trips to the doctor's clinic, as well as less expense. For the medical staff, fewer injections mean savings in time and administration. In terms of public health concerns, it simplifies the immunization calendar, ensures compliance, and makes way for introduction of new antigens. It also makes the immunization program more cost-effective.

Ten Years of Work in One Syringe

    According to Dr. Hessel, Hexavac took at least ten years to develop, test, and ensure the efficacy and immunogenicity of Hexavac.

    Hexavac combines in a single injection all six (nine) antigens in 0.5- mL syringe (Figure 2).

    After 200 different experimental formulations had been tested in animals and at various temperatures, the final formulation was tested. The final product required 400 quality control tests for the active ingredients before it was perfected and deemed ready for human testing.

    Dr. Hessel said their studies showed that the hexavalent combination of antigens is as safe and effective as the vaccines administered separately. "It induces effective protection equivalent to the existing vaccines."

    The clinical trials were conducted in three phases in France, Chile, and Germany, yielding a database--submitted with its application for approval--consisting of 11,500 doses of vaccines administered to 3,900 infants, plus another set of 4,437 booster doses given to toddlers primed with either whole cell or acellular pertussis combination vaccines.

    Dr. Hessel said the safety tests showed that the acellular pertussis vaccine in Hexavac is safer and less reactogenic (whether local or systemic) than the whole cell pertussis vaccine, and that adding the Hib antigen did not alter the reactogenic profile.

    In the Hexavalent vaccine, the level of irritability is only from 15-25 percent, drowsiness around 10 percent, and fever almost insignificant. There was no increase in systemic reaction when Hepatitis B was added to the combination vaccine. There was also no difference in systemic reactions when booster doses were administered.

    In terms of efficacy, trials showed that it achieved all immunogenicity markers and compared well with DTacP - IPV-Hib + Hep B. The booster dose also achieved parallel effects, showing that "the vaccine induces the same priming effects that the immunological memories allow it to have a dramatic booster effect," as explained by Dr. Hessel. When the results of the immunization schedules two, four, and six months were compared with those at two, three, and four months, no differences were noted in terms of immunogenecity.

    Drawing conclusions from the studies, Dr. Hessel said Hexavac is well tolerated, provides seroprotection and seroconversion rates in the same range as those of other acellular pertussis vaccine, generates Hib and IPV response at rates proven efficacious in clinical practice, and has good booster response.

    He concluded: "Hexavac represents the cornerstone of future vaccination programs in the world. It just could be the ultimate step for infant protection."