Effect of Human Immunodeficiency Virus Type 1 Infection on the Antibody Response to a Glycoprotein Conjugate Pneumococcal Vaccine: Results from a Randomized Trial

Faruque Ahmed 0 1 2 Mark C. Steinhoff 0 1 2 Maria C. Rodriguez-Barradas 0 1 2 Robert G. Hamilton 0 1 2 Daniel M. Musher 0 1 2 Kenrad E. Nelson 0 1 2 0 Study sites. HIV-infected persons were recruited from partici pants of the ALIVE (AIDS Linked to Intravenous Experience) study of injection drug users [22], the Baltimore-Washingtonstudy site of the multicenter AIDS cohort study (MACS) of homosexual men [23], the AIDS Clinic at the Johns Hopkins Hospital, and the Special Medicine Clinic ofthe Houston VA Medical Center. Non HIV-infected persons (controls) included ALIVE and MACS parti cipants and staff members of the Houston VA Medical Center 1 Received 31 March 1995; revised 12 September 1995. Presented in part: 32nd annual meeting, Infectious Diseases Society of America, Orlando, Florida, October 1994. Informed consent was obtained from study participants. The protocol was approved by the Joint Committee for Clinical Investigation of the Johns Hop kins Hospital and the Institutional Review Board of the Houston Veterans Affairs Medical Center. Financial support: National Institutes of Health (DA-08004 , DA-04334, AI 35042, and RR-00722); Lederle-Praxis Biologics , Inc. This research is part of a Ph.D. dissertation submitted to the Johns Hopkins University School of Hygiene and Public Health in 1995. School of Public Health , 624 N. Broadway, Suite 125 (Hampton House), Baltimore, MD 21205 2 Departments of Epidemiology and International Health, Johns Hopkins University School of Public Health, and Departments of Pediatrics and Medicine, School of Medicine, Johns Hopkins University , Baltimore , Maryland; Infectious Disease Section, VA Medical Center, and Department of Medicine, Baylor College of Medicine , Houston, Texas Effect of Human Immunodeficiency Virus Type 1 Infection on the Antibody Response to a Glycoprotein Conjugate Pneumococcal Vaccine: Results from a Randomized Trial Adults (n = 282) were randomized to receive either a pneumococcal glycoprotein conjugate vaccine, composed of pneumococcal serotypes 6B, 14, 18C, 19F, and 23F linked to CRM197, or a 23-valent pneumococcal polysaccharide vaccine. Among human immunodeficiency virus (HIV)uninfected persons, conjugate vaccine elicited significantly higher IgG antibody geometric mean titers (GMTs) than did polysaccharide vaccine for serotypes 6B, 18C, and 23F: IgG GMTs were 9.0 versus 4.8, 23.2 versus 5.9, and 15.3 versus 4.4 ltg/mL, respectively. In contrast, the two vaccines elicited similar antibody GMTs in HIV-infected persons: GMTs ranged from 1.3 to 10.8 ltg/mL for all serotypes. Of note, among persons receiving polysaccharide vaccine, antibody GMTs in HIVuninfected and -infected persons with CD4 lymphocytes ~5001ltL were similar. These data underscore the importance of controlled clinical evaluations of newer pneumococcal vaccines in all highrisk groups for whom pneumococcal immunization is recommended and highlight the need for early immunization of HIV-infected persons with currently available polysaccharide vaccines. - Streptococcus pneumoniae (pneumococcus) is an important cause of morbidity and mortality in the United States [1]. A greatly increased incidence of pneumonia and bacteremia due to S. pneumoniae has been observed in human immunodefi ciency virus (HIV)-infected adults [2-6]. The rate ofpneumo coccal bacteremia is ~ lOO-foid higher [7] and the mortality twice as high [8] in HIV-infected patients with AIDS as in HIV-uninfected adults. The protective efficacy of pneumococ cal polysaccharide vaccine against invasive pneumococcal dis ease is estimated to range from 47% to 70% [9-11]. The reduced immunogenicity of polysaccharide vaccine in HIV infected persons [12, 13] suggests that its efficacy might be lower in this population [14, 15]. Although it is recommended that all high-risk persons, including those infected with HIV, receive pneumococcal polysaccharide vaccine, there is a need Sample size. Sample size calculations, based on variance esti mates of antibody levels derived from a pilot study, a significance level of .05, a power of .80, and 20% loss to follow-up, indicated that 92 persons would need to be vaccinated to detect a 2-fold difference in the geometric mean titer (GMT) of antibody or a difference of ;;.30% in the proportion of persons with a ;;.2-fold increase in titer. Because our objective was to evaluate vaccine responses in each of the 3 groups defined by HIV infection status and CD4 cell counts of ;;.2001jlL and <200IjlL, a total of 276 persons was needed. Eligibility. Adults 18-65 years old were eligible for the study. Persons with any of the following conditions were excluded: acute febrile illness at the time of vaccination, immunization with a pneumococcal or diphtheria toxoid vaccine in the previous 5 years or a history of allergic reaction to either vaccine, a history of pneumococcal disease in the last 5 years, poor prognosis for sur vival in the succeeding 6 months, and pregnancy. Vaccines. Conjugate vaccine (lot F252I04; Lederle-Praxis Bi ologics, Rochester, NY) consisted of 10 jlg of capsular polysaccha ride, in the form of 10-20 repeating units of oligosaccharide, from each of five S. pneumoniae serotypes (6B, 14, 18C, 19F, and 23F) covalently linked to CRM197, a nontoxic mutant diphtheria toxin. The 23-valent pneumococcal polysaccharide vaccine (Pnu-Im mune 23, lot 340941; Lederle, Wayne, NJ) is composed of25 jlg of capsular polysaccharide for each S. pneumoniae serotype. The assigned vaccine was injected into the deltoid muscle as a single dose; the subject was not informed as to which vaccine was admin istered. Randomization. The Moses-Oakford algorithm and a table of random numbers were used for randomization, using randomly arranged blocks of sizes 4, 6, and 8 [24]. Randomization was stratified by HIV status (i.e., HIV-uninfected, HIV-infected with ;;.200 CD4 cells/ul., and HIV-infected with <200 CD4 cells/izl.) within each study site. CD4 cell counts, as determined by flow cytometry within the previous 6 months [25], were used. The presence of anti-HIV antibody was ascertained by an ELISA (Ge netic Systems, Seattle), with confirmation by Western blot (Du Pont, Wilmington, DE). Ascertainment of adverse reactions. Participants were ob served for 30 min after immunization for the occurrence of imme diate hypersensitivity reactions. Each vaccinee was requested to record any adverse reactions for the first 7 days after immunization on a form designed for this purpose. Samples and serologic assay. Venous blood was collected just before and 1 month after immunization. Blood samples were cen trifuged within a few hours, and the resulting sera were frozen at - 20C. Serotype-specific IgG antibody to pneumococcal capsular polysaccharide was determined by ELISA [26] after sera were adsorbed with pneumococcal C-polysaccharide [27]. Each sample was tested in dilutions of 1:1000, 1:4000, and 1:16,000. The optical density was converted to micrograms per milliliter of I (...truncated)