Evaluating the immune response to combination vaccines.

Assessment of the immune responses to combination vaccines in the United States has generally been based on randomized, controlled comparative trials, with such studies designed to rule out predefined differences. In designing clinical studies of the immune response to combination products, attention should be directed toward selecting the appropriate immunologic end points and control groups. Acceptable differences in immune responses between combination and control groups should be predefined, and an adequate statistical plan should be developed. In many cases, it may be necessary to evaluate simultaneous administration of other recommended vaccines, assess schedule changes for 1 or more components of a combination, and bridge immunologic data obtained from international studies to the population of the United States. We discuss the use of immunogenicity studies to support the licensure of combination vaccines when field efficacy studies are either not possible or not required and highlight some recent experiences with combination vaccines containing Haemophilus influenzae type b polysaccharide conjugates.

Analysis of studies to evaluate immune response to combination vaccines.

The development and evaluation of new combination vaccines is an important public health endeavor. Trials to evaluate these vaccines are customarily designed and analyzed as noninferiority studies. We explain the concept of noninferiority and highlight important issues that can be challenging in the statistical evaluation of these vaccines. Topics covered include end points, hypotheses, and analyses for comparing geometric mean concentrations (or titers) of antibody and proportion of vaccine recipients responding; covariate adjustment; the problem of multiplicity and its impact on sample size; and choice of a meaningful difference to rule out.

Intent-to-treat analysis and preventive vaccine efficacy.

While the intent-to-treat (ITT) concept has often been discussed and debated in the literature with respect to randomized, placebo-controlled therapeutic trials, there has been little discussion of this issue in the context of preventive vaccine efficacy trials. ITT analysis has traditionally played a minor role (if any) in the latter trials. This paper discusses the ITT approach to analysis in randomized superiority trials of preventive vaccine efficacy, using clinical endpoints. Data are presented from published literature as well as from a simple mathematical model. The data suggest that when compliance and efficacy are high, both ITT and "per-protocol" approaches generally lead to similar conclusions regarding the acceptability of a vaccine for use in a population. However, when compliance is low, the ITT and per-protocol estimates of vaccine efficacy can be widely disparate. ITT and per-protocol analyses address unique and relevant scientific questions, and often both will be informative in evaluating preventive vaccines.

Clinical safety evaluation of combination vaccines.

The development plan for new combination vaccines should include clinical studies designed to provide an adequate safety database (as well as efficacy data) to support licensure. Ideally, randomized studies to compare the safety of the combination vaccine with the separately administered components (or already licensed combinations of components) should be performed. For new combination vaccines having components with proven efficacy, comparative immunogenicity data may provide a sufficient basis to support efficacy, precluding the need for a large efficacy study. In the absence of the safety database that would have been derived from such an efficacy study, it is important to conduct a comparative safety study with a sample size suitable for the evaluation of less common adverse events. For large safety trials, a simplified design where only a subset of subjects is assessed in detail for the more common adverse events may be appropriate.

Childbearing and Bongaarts indices for Coale-Trussell's model fertility schedules.

PIP: It is often important to measure the determinants which have direct impact upon the fertility and childbearing process, especially when information on such mechanisms is nonexistent or defective. Methodologies have therefore been developed to that end over the last two decades. Each development, however, addressed only one or some aspects of the complete process of fertility and childbearing in a society. A comprehensive picture is often desired. This paper provides a broader knowledge of the mechanisms which underlie the reproductive patterns in human populations by combining and linking various recent methodologies and models. The following methodology is proposed: age-specific fertility rates are first obtained from Coale-Trussell model fertility schedules, then used in the childbearing model to compute childbearing indices. Fertility-inhibiting indices finally are estimated as functions of the childbearing indices, using El-Khorazaty's multivariate regression model.^ieng

Deleterious effect of thimerosal on the potency of inactivated poliovirus vaccine.

High-potency inactivated poliovirus vaccine (eIPV) was combined with diphtheria-tetanus-pertussis (DTP) vaccine containing thimerosal as a preservative to simulate the performance of a potential tetravalent vaccine. Neither type 1 nor type 3 poliovirus antigens appeared to be affected by thimerosal after exposure for 1 h at 37 degrees C as measured by enzyme-linked immunosorbent assay (ELISA). One epitope on the type 2 antigen was damaged within 5 min of exposure; however, the overall potency was unchanged when measured using a polyclonal antibody preparation. Exposure to thimerosal at 37 degrees C decreased the potency of all three poliovirus types to well below the level caused by heat deterioration alone in 1-2 days and to 0% after 16-17 days. At 25 degrees C, the potency of type 1 poliovirus decreased by 46% in 1 day, whereas poliovirus types 2 and 3 were stable for 1 week. Storage of eIPV at 4 degrees C in the presence of thimerosal reduced the potency of type 1 poliovirus antigen to undetectable levels after 4-6 months. Type 2 and 3 antigens were less markedly affected by 8 months of exposure to thimerosal at 4 degrees C. The loss of potency of type 1 as measured by ELISA was paralleled by a reduced level of neutralizing antibodies in mice injected with these preparations. The results obtained from testing eIPV in combination with DTP and thimerosal were generally similar to those obtained using eIPV with thimerosal. It remains to be seen to what extent thimerosal will affect the immunogenicity of eIPV in humans when injected as combined eIPV-DTP vaccine.

Fertility-inhibiting indices in the Arab world.

PIP: Bongaart's model for estimating fertility levels that was not available in Arab countries. In this study, El-Khorazaty's model was used to determine fertility-inhibiting indices for the Arab countries with available age-specific fertility rates (ASFR) and to compare differences regionally, residentially, and nationally. The value of total fecundity (TF) was set at 17 rather than at the Bongaart's recommended 15.3, in order to avoid the negative values for percentage reduction from TF obtained by Bulatao. Childbearing indices provided projected estimates of the mean age of first and last birth and the projected length of the reproductive period experienced by a new cohort of women with a specified ASFR. These estimated and UN estimates were used to indirectly estimate Bongaarts indices. Estimates were generated for Algeria, Bahrain, Egypt, Iraq, Jordan, Kuwait, Lebanon, Libyan Arab Jamahiriya, Mauritania, Morocco, Qatar, Sudan, Syrian Arab Republic, Tunisia, United Arab Emirates, and Yemen Arab Republic. 8 of these 16 countries showed fertility decline for the periods indicated: Egypt, Lebanon, Morocco, and Tunisia with declines due top contraceptive use and lower proportions married; Bahrain and Kuwait due to lower proportions married; and Sudan and Yemen to lactational infecundability. Increases in fertility were found in Mauritania, Qatar, and the United Arab Emirates, due to lower lactational infecundability, higher proportions married, and lower contraceptive used; and in Libyan Arab Jamahiriyha due to shorter breast feeding durations, higher proportions married, and unmeasured factors. Little change was represented in Algeria, Iraq, Jordan, and Syria until the late 1970s. The total fertility rate between 1980-85 for all Arabs was 6.2. The most important of Bongaart's intermediate fertility variables in reducing fecundity was proportion married, responsible for 27% of the decline in TF with an index of .760. The least important was contraceptive usage, accounting for 16% with an index of .851. The Gulf countries followed a different pattern, but contraception was still the least important. Urban-rural status was important only in Egypt, Jordan, Syria, and Morocco. Educational estimates were not reliable.^ieng

Statistical modeling of selected aspects of the childbearing process with application to World Fertility Survey countries.

"A mathematical model for estimation of certain aspects of the childbearing process, which requires only data on age-specific fertility rates, is developed. Synthetic maternal childbearing indices, namely, mean ages at first and last birth, length of reproductive life span, inter-birth spacing, and proportion of childless women, in addition to the well-known mean age at childbearing, for the WFS [World Fertility Surveys conducted in developing] countries are obtained using the proposed model. The indices are free from age truncation effects, and, under certain assumptions, provide information about a cohort's completed fertility before the women stop reproducing. The effects of women's residence and education on fertility are also examined." (SUMMARY IN FRE)

The span of reproduction in Egypt.

This study shows long reproductive spans to be associated with low levels of women's education, rural residence, remarriage, early marriage age, and high parity. Effects are statistically significant.

PIP: The age at which childbearing is ended determines the reproductive span's (RSPAN) length. In Egypt, there is not much birth spacing; most women use birth control methods only after they achieve their desired family size. A regression model is used to analyze associations between women's education, "marital dissolution." residence characteristics and the length of the reproductive span in Egypt. Data from the 1980 Egyptian Fertility Study (EFS) were used. The hypotheses were that : 1) better educated women tend to have shorter RSPANs; women who live in rural areas spend more time in childbearing than those who are urban residents; 3) dissolution of marriages without remarriage tends to make the RSPAN shorter; 40 marital disruption and then getting married again tends to lengthen the RSPAN. The mean length of the RSPAN in years by independent variables is given for women of ages 45-49 in Egypt in 1980. The Spearman correlation coefficients for independent variables for women of the same ages are also given in tabular form, as are the results of regression analysis for women aged 45-49, Egypt, 1980. Years of schooling had a negative effect on the length of the RSPAN, significant at the 0.05 level. Current residence in rural areas is correlated with linger RSPANS than normal. Women whose 1st marriage never dissolved, have RSPANs not significantly changed for the mean (p- value=0.1282). Those whose marriages had dissolved and remarried had the longest RSPANs--about 1.5 years more than the average. RSPAN decreased as age at 1st marriage increased. Higher parity was associated with longer spans. A lowering of the age at last birth can be encouraged to reduce high fertility.

Maternal age at last birth in Egypt.

PIP: To assess the effects of women's education, residence, and marital experience on their age at the birth of their last child, a proportional hazards regression model was applied to 1980 Egyptian Fertility Survey (EFS) data. The detailed data include the date of birth of each child for every women interviewed, and the woman's date of birth and age at interview. Age at last birth was examined by regression analysis on birth history and socioeconomic information. 4 hypotheses were tested: women who are well educated have a greater probability of ending childbearing earlier than women with less education; women in rural areas have a higher probability of having their last child at older ages than urban women; marital disruption without remarriage lowers the probability of older maternal age at last birth; and marital disruption with remarriage increases the probability that a woman stops reproducing at an older age. The overall chi-square indicates a significant regression. All coefficients were significant, except the coefficient for women with intact 1st marriages. Women with more education had a greater probability of ending childbearing earlier than women with less education. Rural women tended to have their last children at ages significantly older than overall age at last birth. Current residence in urban areas had the opposite effect. The coefficient for those with intact 1st marriages was insignificant, meaning that the mean age at last birth for this group of women was not much different from the overall mean. Remarried women tended to end childbearing at ages significantly older than the overall average age at last birth, suggesting that these women tended to have children by their new husbands. Those with dissolved 1st marriages who had not remarried had a higher probability of ending childbearing earlier than did older women. Marriage age and final parity had highly significant negative coefficients; as marriage age and number of children born increased, so did the "survival" time or the age at last birth. Results from the hazards model indicate that the effects were as anticipated. The median age at last birth for the total sample of women aged 45-49 was 45-49 years. The median age at last birth was about 2 years older for rural compared to urban women. Illiterate women had the oldest median age at last birth of the education groups. There was little differences between median ages at last birth for women with intact 1st marriages and those whose 1st unions were dissolved and who had remarried. The median age at last birth increased with final parity.^ieng

Childbearing indices in the Arab world.

PIP: Patterns and tempo of entry into marriage and motherhood, birth spacing, and exit from the childbearing process play significant roles in the realization of societal level fertility. Childbearing models using quantum measures of period fertility, namely, age-specific fertility rates, to develop projected temporal indices of the childbearing process have been extended to 16 Arab countries representing over 90% of the population of the Arab world. Comparisons of 2 Arabian Gulf countries revealed diverse levels and patterns reflecting the populations' backgrounds, levels of societal development, and the stage of demographic transition. Results for Arab countries and national populations indicated younger projected ages at 1st birth, older projected ages at last birth, longer projected reproductive spans, and shorter projected birth spacing than expatriate populations. It is suggested that reproductive span is the best predictor of fertility, as well as of mortality and socioeconomic factors, at the societal level. Countries in which childbearing is initiated at earlier ages also show termination of childbearing at later ages and thus tend to have relatively higher fertility and mortality levels, poorer health conditions, and unfavorable social environments.^ieng

A parity-specific fertility table for Egypt: application of Nour's method.

"In the present paper, a method of constructing a fertility table based on the observed current parity distribution, developed by Nour (1984), is used to obtain a parity-specific fertility [rate] for Egypt....Nour's method is based on the assumption that women at a given parity and age will have the same fertility behavior regardless of their previous experience." Data are from the 1980 Egyptian Fertility Survey.