December 1996
BETHESDA, Md. — The Food and Drug Administration's (FDA) Vaccines and Related Biological Products Advisory Committee recently requested more data on the combined diphtheria-tetanus-acellular pertussis (DTaP) vaccine presented by Amvax, a subsidiary of North American Vaccine.
Amvax asked for approval to market its vaccine for the primary immunization series in infants 2 months, 4 months, 6 months and 15-18 months of age, and for simultaneous administration with polio, Haemophilus influenzae type b (Hib), hepatitis B and measles-mumps-rubella vaccines.
The committee commented that the safety data was adequate for a fifth dose of NAVA DTaP following a primary series of whole-cell pertussis vaccine with either whole-cell or acellular pertussis vaccine as a fourth dose.
Concerning the fourth dose booster, the committee suggested the data of only 42 subjects was not enough to support approval of a booster indication.
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"The numbers are relatively small. I am a bit uncomfortable with the data. The data that are available so far are reassuring, but I would prefer to see larger numbers," said temporary committee member Dixie Snider, MD.
"The efficacy rates for a 2-4-6 month schedule are not clear," added temporary committee member Thomas R. Fleming, PhD.
The committee also stated the safety database of the 2 month, 4 month and 6 month schedule was adequate for common adverse events and fever, but additional safety data for the fourth and fifth consecutive doses of the DTaP vaccine as well as for a fourth dose of vaccine following three doses of DTP would be helpful.
Another question concerning the Amvax study included calculations of efficacy and definition, said David T. Karzon, MD, temporary committee member. The highest values are obtained when calculations are restricted to full blown cases of typical pertussis and are lower in modified milder cases. For example, calculations using only cases defined as paroxysmal cough lasting 21 days or longer, efficacy is 72%. For milder cough lasting seven days or longer, efficacy is 54%.
"It's like comparing apples and oranges," he said.
The single-component DTaP vaccine (Certiva, Amvax), consists of a single purified pertussis toxoid that has been irreversibly detoxified with hydrogen peroxide. According to study results, the acellular pertussis vaccine had an efficacy rate varying between 71% and 77%, depending on the definition of pertussis.
The World Health Organization's (WHO) definition of pertussis includes a paroxysmal cough lasting at least 21 consecutive days with one of the following: culture-confirmed Bordetella pertussis, a statistically significant increase in IgA or IgG antibodies against pertussis toxin or filamentous hemagglutinin; or contact with a household member with culture-confirmed B. pertussis who began coughing 28 days before or after onset of cough in the study person.
The estimate of efficacy for WHO-defined cases during the main period of the follow-up was 72% in Europe based on a three-dose schedule at 3 months, 5 months and 12 months. However, to achieve comparable efficacy rates in the United States, the dosage must increase to four doses at 2 months, 4 months, 6 months and 15 months of age, according to the committee's statement.
Although vaccination schedules differ between United States (2 months, 4 months and 6 months of age) and European countries (3 months, 5 months and 12 months), committee members did agree the schedules are close enough to produce the same results.
Bridging studies conducted by Amvax demonstrated the comparability of immune responses to all antigens using a 3-, 5- and 12-month and 2-, 4- and 6-and 15-month schedule.
Many children in the United States are late getting their vaccinations and are probably closer to the European vaccination schedule, said FDA committee member Caroline B. Hall, MD.
Overall, the results suggest the vaccine is less reactogenic than the whole-cell vaccine in studies from 1986 through 1996 conducted in the United States, Denmark and Sweden with more than 47,000 individuals vaccinated.
The U.S. clinical studies involved approximately 3,000 healthy infants in various sites. In one safety and immunogenicity study, approximately 1,300 infants were randomized to receive the monocomponent pertussis toxoid vaccine or a U.S. licensed whole-cell DTP vaccine. The majority of these infants were immunized concurrently with a Hib conjugate vaccine, a hepatitis B vaccine and a trivalent oral polio vaccine.
Investigators did not find serious adverse events to be vaccine related, and the incidence of fever, local redness, pain and swelling were significantly lower with the acellular pertussis vaccine than after immunization with the whole-cell pertussis vaccine.
Of the infants who received four doses of the acellular pertussis vaccine concurrently with polio, hepatitis B and Hib vaccines, 100% achieved protective levels of antibodies against each of these vaccines, according to Amvax reports.
After reviewing these results, the committee stressed the importance of data from an ongoing mass vaccination trial in Sweden for establishing the safety of the vaccine.
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