Developing and deploying pneumococcal and haemophilus vaccines

Caesarean section and perinatal HIV transmission: what next? know how and when human immunodeficiency virus (HIV) is transmitted from a pregnant infected mother to her baby. In developed countries, the perinatal transmission rate in prospective cohort studies ranges from 14 to 32%. In these studies there was no significant relation between infection of the offspring and mode of delivery, although in the larger cohortss°6 the percentage of infected children was lower after caesarean section. Villari and colleagues8 have now conducted a meta-analysis of published data,1-7,9 and they found a significant difference between operative and vaginal delivery, with 14% vs 20% of babies being infected (p = 0-044). This latest result, being derived from observational studies, cannot indicate definitively whether caesarean section reduces perinatal HIV transmission. If caesarean section is to be effective in this respect, the baby must be uninfected up to that point. Several findings suggest that most children acquire infection late in pregnancy or during delivery. Thus, HIV-associated clinical manifestations and immunological abnormalities are usually absent at birth in children ultimately shown to be infected; virus transmission is higher in firstborn than in secondborn twins;9 and, even with the most sensitive techniques, HIV is detectable in the first few days of life in only 30-50% of infected infants compared with 90% by age 3 months. Conversely, newborn babies with proven infection do not have clinical signs or immunological abnormalities, the differential transmission rate between twins is still present in those born by caesarean section,9 and reduced HIV replication in fetal tissues or its initial yield in peripheral lymphoid tissues could account for its absence in cord blood. If most children acquire infection in the peripartum period, caesarean section might be preventive in several ways-above all, avoidance of massive exposure to infectious maternal blood and vaginal fluid during the passage through the birth canal, with a potential additional risk from certain obstetric procedures such as episiotomy and instrumental delivery. However, if this were a main route of transmission, one would expect a more pronounced protective effect. According to the meta-analysis, 16 (95% CI 9-79) HIV-infected women must deliver by caesarean section to prevent 1 case of perinatal infection. One explanation is that caesarean delivery reduces, but does not eliminate, maternal blood contact. Perhaps the benefits of caesarean section are underestimated by current data. Elective caesarean delivery prevents maternal-fetal blood transfusions that might occur during the remainder of the pregnancy and labour, and also prevents exposure to contaminated secretions after rupture of membranes. Blood mixing across the placenta increases towards the end of gestation, peaking during labour, and there is evidence of other ascending infections after membrane rupture. Emergency caesarean sections have been done in the context of full-term pregnancy, protracted labour, and prolonged rupture of membranes. Elective procedures have preferentially been carried out in women with symptoms and with high viral burden,sconditions associated with an increased risk of HIV transmission.5,6 Additionally, the confounding effects of this and other variables have seldom been evaluated by multivariate

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analysis. Therefore, the risk directly linked to each mode of delivery may have been under or over estimated. Is it time to embark on randomised controlled trials? The main difficulty lies with ethical obstacles, since caesarean section carries some risks for both mother and offspring. Another difficulty may arise from the sample size needed for such trials. A specific randomised study has started in Italy, but the goal is unlikely to be reached in reasonable time without recruitment of patients from other countries. Finally, studies are in progress or shortly to start on the efficacy of other preventive measures during pregnancyeg, antiviral therapy, and/or polyclonal and/or monoclonal anti-HIV IgG. Investigators may find these perspectives more attractive. Meanwhile, the largest observational studies are attaining an individual statistical power similar to that of Villari et al. If confirmatory (as the latest preliminary data emerging from the Italian register for HIV infection in children6 seem to suggest), these results may soon provide the necessary impetus for randomised trials.

Pier-Angelo Tovo Department of Paediatrics, University of Turin, Turin, Italy Blanche S, Rouzioux C, Guihard Moscato ML, et al. A prospective study of infants born to women seropositive for human immunodeficiency virus type 1. N Engl J Med 1989; 320: 1643-48. 2 Hutto C, Parks WP, Lai SH, et al. A hospital-based prospective study of perinatal infection with immunodeficiency virus type 1. J Pediatr 1991; 118: 347-53. 3 Lindgren S, Anzen B, Bohlin AB, Lidman K. HIV and child-bearingage: clinical outcome and aspects of mother to infants transmission. AIDS 1991; 5: 1111-16. 4 Kind C, Brandle B, Wyler CA, et al. Epidemiology of vertical transmitted HIV 1 infection in Switzerland: results of a nationwide prospective study. Eur J Pediatr 1992; 151: 442-48. 5 European collaborative study. Risk factors for mother-to-child transmission of HIV. Lancet 1992; 339: 1007-12. 6 Gabiano C, Tovo PA, de Martino M, et al. Mother to child transmission of HIV: risk of infection and correlates of transmission. Pediatrics 1992; 90: 362-74. 7 Nair P, Alger L, Hines S, Seiden S, Hebel R, Johnson JP. Maternal and neonatal characteristics associated with HIV infection in infants of seropositive women. J Acquir Immune Defic Syndr 1993; 6: 298-302. 8 Villari P, Spino C, Chalmers TC, Lau J, Sacks S. Cesarean section to reduce perinatal transmission of human immunodeficiency virus. Online J Curr Clin Trials 1993; 2: July 8 doc no 74. 9 Goedert JJ, Duliège A, Amos CI, et al. High risk of HIV-1 infection for first-born twins. Lancet 1991; 338: 1471-75. 1

Developing and deploying pneumococcal and haemophilus vaccines Many scientists have taken an interest in the new pneumococcal polysaccharide-protein conjugate vaccines that are immunogenic in infants. Pneumococcal vaccines consisting of capsular polysaccharides have been available since the 1960s, but the older products were neither immunogenic nor effective in infants, the age group with the highest rates of invasive pneumococcal disease. Since immunity to pneumococcal disease is serotype specific, composition of the new conjugate vaccines should match the distribution of pathogenic serotypes in areas where they are to be used. A meeting of twenty-six experts in pneumococcal disease was held at the Rockefeller Foundation in New York to review the available data on and Haemophilus influenzae serotype distributions in developing regions and to consider how additional serotype data might be obtained.

pneumococcal

Data from over 2000 isolates were summarised in a review of invasive pneumococcal serotypes from children in developing regions. There are considerable variations in serotype distribution between geographic regions, within geographic regions, and even within single countries, and also temporal variations within a single region or country. Clinicians from South Asia and sub-Saharan Africa (except South Africa) have reported relatively few pneumococcal isolates. In general, the five most common serogroups (1, 5, 6,14,19) account for 50-60 % of all invasive isolates in most regions, but vary in rank order in different regions. Two formulations of pneumococcal conjugate vaccines are currently in phase I and phase II trials in developed countries. One vaccine, formulated for developing countries, includes serotypes 1.5.6B, 14,18C, 19F,23F,the other, formulated for industrial countries, incorporates serotypes 4, 6B, 9B, 14, 18C, 19F, and 23F. When these vaccines are compared with the spectrum of pneumococcal serotypes isolated from children of developing regions, they show levels of coverage of 54-73% and 46-670,

Steinhoff MC, Edwards K, Keyserling H, Johnson C, Madore D, Hogerman D. Immunogenicity and safety of 3 bivalent S pneumoniae conjugate vaccines in young children. Program and Abstracts of the 32nd Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington DC;

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1992: 325. Robbins RB, Austrian R, Lee CJ, et al. Considerations for formulating the second-generation pneumococcal capsular polysaccharide vaccine with emphasis on the cross-reactive types within groups. J Infect Dis 1983; 148: 1136-59. Institute of Medicine. New vaccine development: establishing priorities. Vol II. Diseases of importance in developing countries. Washington, DC: National Academy Press, 1986: 357-75. Riley ID, Lehmann D, Alpers MP. Pneumococcal vaccine trials in Papua New Guinea: relationships between epidemiology of pneumococcal infection and efficacy of vaccine. Rev Infect Dis 1991; 13 (suppl 6): 535-41. Mastro TD, Ghafoor A, Nomani NK, et al. Antimicrobial resistance of pneumococci in children with acute lower respiratory tract infection in Pakistan. Lancet 1991; 337: 156-59. Funkhouser A, Steinhoff MC, Ward J. Haemophilus influenzae disease and immunization in developing countries. Rev Infect Dis 1991; 13

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respectively. The WHO acute respiratory infection (ARI) programme supporting evaluations of antimicrobial resistance of pneumococci in several regions, and will also develop serotype data. Studies of serotype distribution are to be undertaken in Latin America by the Regional System for Vaccines in the Americas (SIREVA) project of the Pan American Health Organization, and are planned in India by the International Clinical Epidemiology Network. Some participants at the meeting felt that additional data on serotype distribution was desirable, especially for Southern Asia and sub-Saharan Africa; others held that efficacy trials of current pneumococcal conjugate vaccines should be initiated, because documentation of efficacy would stimulate the collection of serotype data. A septavalent pneumococcal conjugate vaccine containing serotypes 1, 5, 6B,14,18C,19F, and 23F is likely to provide protection against 50-75% of childhood serotypes in most developing regions. How many invasive isolates are needed to guide decisions on vaccine formulation? A sample of 200 such isolates collected over 1-2 years at a single site should be adequate to determine the top 5-7 serotypes for a vaccine. Evaluation of the additional coverage afforded by including 3-5 more serotypes or assessment of temporal variation will require larger samples and longer periods. Preliminary studies and field efficacy trials of new pneumococcal conjugate vaccines will provide valuable information on the rates of disease due to pneumococcus, in addition to assessing vaccine impact on pneumococcal disease. Hospital and clinic surveillance studies will provide useful information on serotype data. Because the diagnosis of pneumococcal disease is difficult, we need better techniques for detection, both to define the rates of disease and to facilitate vaccine efficacy trials. Clinical specimens (such as serum and cerebrospinal fluid) from ongoing studies should be saved for evaluation of newer diagnostic tests. The ARI control programme at WHO, Geneva, or the Childhood and Respiratory Diseases Branch at the Centers for Disease Control and Prevention, Atlanta, can be contacted for information on diagnostic test development or studies on pneumococcal isolates.

Competing in drug safety

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Mark C Steinhoff School of Hygiene and Public Health, John Hopkins University, Baltimore, Maryland, USA

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At the stage when a new drug is released onto the market there is only limited evidence about its safety in human beings. This fact is well recognised, and serves to emphasise the necessity of collecting safety information as quickly as possible once the agent is in routine clinical use. These points are noted by Inman and Pearce in their paper this week, but the key issue raised by these researchers is that promotional postmarketing surveillance (PMS) studies conducted by the pharmaceutical industry are competing for both patients’ and doctors’ involvement with

prescription event monitoring (PEM). They suggest that PMS studies have been directly responsible for a reduction in response within the PEM programme, but they do not present evidence to back this assertion. They cite Waller et all as showing the ineffectiveness of the company PMS studies. However, the study by Waller et al showed that the main drawback with company PMS studies was failure to recruit sufficient patients, a problem that PEM has also encountered with some drugs. Other difficulties that they mention-eg, causing bias by promotion due to the study-can be avoided by proper study design, so one cannot conclude that all PMS studies are valueless. Nevertheless, there is a continuing dilemma in that the commercial need to promote a new drug, by whatever means, is always likely to cause biased drug use, which will be reflected in PEM. Conversely, PMS studies, which can theoretically avoid recruitment bias and include controls, will generally recruit only a sample of drug users and take longer to reach an adequate size for safety investigation. Postmarketing safety of drugs may be studied by various methods-eg, cohort studies, either as regular surveys (PEM in the UK, the Intensive Medicines Monitoring Programme in New Zealand), or by specifically designed cohort studies (PMS); by the use of multipurpose databases such as MEMO or VAMP; or by spontaneous reporting supported by case-control studies. For early, optimum identification of safety problems the most obvious approach is to gather a large cohort of patients who have been prescribed the drug in question (10000 is a reasonable number) and to follow them up for a sufficient time, though

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