Both HIV-1-infected patients and HIV-seronegative control subjects generated appreciable mean increases in each serotype-specific antibody (Table 2, Fig. 1). Type 14 was the most reliably immunogenic serotype in both clinical groups. Differences in the mean increases between groups were significant only for type 6B, but the proportion of HIV-1-infected vaccinees with increases greater than twofold was consistently lower compared with that in control subjects.
A 41-year-old Ugandan woman received pneumococcal vaccine in November 1994. At that time she complained of chronic cough and suffered recurrent documented fevers that had lasted more than a month (WHO clinical stage 3) . Her CD4+ T cell count was 216 × 106 cells/l. Thirteen months after vaccination she visited the clinic with a history of fever and worsening cough in the preceding 3 days associated with production of purulent sputum. Examination revealed newly present rales at the right lung base, a temperature of 39°C, pulse 120 beats/min and respiratory rate 32/min. Sputum and blood cultures grew S. pneumoniae. She made an uneventful recovery with a single parenteral 5 million unit dose of benzylpenicillin and subsequent oral amoxicillin 500 mg three times daily for 5 days. The organism was penicillin-sensitive (based on oxacillin disc susceptibility) and capsular serotype 1 (based on the Quellung reaction, graciously performed by Dr Robert Austrian), a vaccine serotype that causes up to half of cases of invasive pneumococcal disease in sub-Saharan Africa [3,15]. Sera were obtained acutely and after 4 weeks of convalescence.
A 34-year-old Ugandan woman received vaccine in November 1994. She gave a history consistent with episodes of sinusitis occurring at least twice in the previous 6 months (WHO clinical stage 2). Her CD4+ T cell count was 494 × 106 cells/l. Fourteen months after vaccination she presented with a 6-day history of fever, left pleuritic chest pain and new cough productive of purulent sputum. On examination, she had bronchial breathing at the left lung base, fever of 37.8°C, pulse 100 beats/min, and respiratory rate 18/min. A chest radiograph confirmed the presence of left lower lobe pneumonia. Sputum culture grew only S. pneumoniae. She received a 5-day course of oral amoxicillin 500 mg three times daily. When seen 3 weeks later, she had improved and returned to work. The organism was penicillin sensitive and capsular serotype 13, a non-vaccine serotype. Peri-event sera were not available.
Serum killing activity
The ability of sera from three randomly selected control subjects and six HIV-1-infected patients to support complement-mediated killing by phagocytes of serotype 1 S. pneumoniae increased appreciably 4 weeks after vaccination compared with pre-vaccination values (Fig. 2; top two panels); the titers varied within each group. In contrast, sera from the two HIV-1-infected vaccine failures, Patients 1 and 2, showed no such ability to mediate killing of this organism in either pre- or post-vaccination sera (Fig. 2; left bottom panel). In addition, even after natural bacteremic infection with S. pneumoniae serotype 1, sera from Patient 1 showed no detectable activity to kill the organism (Fig. 2; right bottom panel). As expected, no change was noted in serum killing activity against serotype 13 (a nonvaccine serotype) in either of the two HIV-1-infected patients or the three HIV-seronegative control subjects (not shown).
We have shown that patients at appreciable risk of invasive pneumococcal disease, HIV-1-infected adults in East Africa, can be efficiently recruited and reliably followed for a prospective vaccine trial. These patients generate a significant antibody response to three of four capsule types contained within the 23-valent polysaccharide vaccine, including serotype 1, which comprises up to half of serious pneumococcal infections in this area . These responses appear independent of CD4+ T cell counts, as described in other populations, but are lower than those produced by the HIV-seronegative control subjects [13,16].
Antibodies directed against the polysaccharide capsule are the principal mechanisms of defense against invasive pneumococcal infection . The importance of these antibodies in protection is supported by the observations that HIV-1-infected Patient 1 failed to generate functionally active capsule-specific antibodies to serotype 1 after immunization; she subsequently developed pneumococcal bacteremia with that serotype and failed to produce functionally active antibodies to the organism after infection. That other HIV-1-infected patients did respond to the vaccine, as assessed by ELISA and the killing assay, and that quantitative antibody responses to capsular polysaccharides in the vaccine correlate with functional activity [13,17] suggest that vaccination may be helpful in protecting against serious invasive pneumococcal disease (e.g., bacteremia, meningitis) at all stages of HIV-1 infection. Nevertheless, as with Patient 1, there may be a subgroup of HIV-1-infected individuals who are unable to generate a response to capsular polysaccharide antigens, whether presented in vaccine or in the organism itself during natural infection. Identifying the specific mechanisms of unresponsiveness and the proportion of patients who show such impaired responses is important for several reasons.
First, the number of individuals with such inadequate responses in a cohort of patients and their contribution to the excess rates of pneumococcal disease seen in HIV-1-infected adults will be a powerful predictor of whether pneumococcal polysaccharide vaccination will be effective as a preventive public-health strategy. If, as with Patient 1, there is a small subgroup of HIV-1-infected adults at extremely high risk who account for most cases of disease and they do not respond to vaccination, it is unlikely that we will see an impact of vaccination at the population level. It is more likely, however, that the cases we have reported represent the extreme end of the distribution of impaired humoral immune response to polysaccharides. Among HIV-1-infected women in Nairobi, the frequency and magnitude of responses to vaccine among those with prior pneumococcal bacteremia was similar to those in women without previous pneumococcal disease . These data suggest that identifying a clear subgroup of non-responders to polysaccharide antigens at increased risk of pneumococcal disease may be difficult as the risks may be multifactorial . A prospective trial is now in progress in Uganda to establish whether vaccination will demonstrate a protective effect at the population level and whether assessment of vaccine-specific immunological responses correlate directly with clinical outcome.
Second, any protective effect of the vaccine will only relate to the serotypes of S. pneumoniae contained within the vaccine. Serotype 13, identified in Patient 2, is a non-vaccine type but is thought to be uncommon in East Africa. The distribution of serotypes included in the current vaccine were determined predominantly from data from developed countries but appear to represent over 80% of significant isolates found in HIV-1-infected adults in Nairobi, Kenya, and South Africa [3,19]. The public-health impact of vaccination will be limited if a high proportion of disease is caused by nonvaccine serotypes irrespective of any serotype-specific efficacy. This is a particular problem when fewer serotypes can be included in newer protein–polysaccharide vaccines. Consideration of local results on the prevalent serotypes causing disease will be important in planning vaccination programs.
Although pneumococcal vaccine efficacy may be limited by the immunogenicity of antigens in the population at risk and by the appropriateness of the vaccine serotypes selected, rigorous evaluation of vaccine efficacy in East Africa does not appear to be limited by patient recruitment or compliance. In Entebbe, access to a population of HIV-1-infected adults is good. The TASO clinic in Entebbe serves a large number of HIV-1-infected individuals as the only center primarily caring for their needs in the district. Interest in pneumococcal vaccination was strong and recruitment rapid (October/November 1994) because (i) vaccination (irrespective of type) is perceived positively, a consequence of the work of UNEPI (United Nations Extended Program of Immunization) and other organizations promoting childhood vaccination; and (ii) pneumococcal vaccination was considered by the clients as a relevant intervention for HIV-1-infected adults, when previously no other prophylactic strategies existed or were affordable. The willingness and enthusiasm of individuals to take part were also reflected in excellent follow-up and low default rate, both of which contributed to a successful trial. There are probably several reasons for these achievements. The use of an acceptable product may fill a perceived need in a population. Access to an established centralized clinic, TASO, is appealing because of its holistic approach to care and its provision of counseling, social, and subsidized medical services, which are unavailable elsewhere in the district. The geographically contained region around Entebbe and the surrounding settlements, which are situated on a peninsula into Lake Victoria, provided a circumscribed population. Finally, migration was low because, for many residents, Entebbe is their family home and where they will be buried. Consequently, they will remain in the area for sickness and terminal care. Indeed, the principal losses to follow-up were as a result of low rates of survival, which were in turn a consequence of the large proportion of individuals with relatively advanced diseases as measured by low CD4+ T cell counts. Recruitment for the vaccine efficacy trial will need to adjust sample sizes to achieve adequate observation time to account for the poor survival of HIV-1-infected patients attending this center. Nevertheless, high rates of pneumococcal disease should help to establish whether the vaccine has a substantial impact on rates of pneumococcal disease.
Our estimated rates of S. pneumoniae infections, 13 per 1000 person-years of observation (95% CI, 2–49) in vaccinated adults, may under-represent the true rates of disease in this population. Events may have been missed in the first 9 months when diagnostic microbiology facilities were under development. As a result, we cannot determine vaccine efficacy. However, disease rates will probably be high enough to support a randomized placebo-controlled trial. If rates of pneumococcal disease are closer to those found in neighboring Nairobi, Kenya (25–42 per 1000 person-years) , a 66% efficacy of the vaccine would be identifiable with sample sizes of approximately 500 subjects in each arm.
In summary, prophylaxis for opportunistic infections has had a dramatic impact on HIV-1 care and survival in the developed world. However, many of these regimens would be inappropriate in the developing world, where Pneumocystis carinii, cytomegalovirus, and Mycobacterium avium complex disease are infrequently reported . In venues such as sub-Saharan Africa, cost-effective prevention of pneumococcal disease, along with tuberculosis, non-typhi salmonellosis, and cryptococcosis, is a priority. The currently available polysaccharide vaccine offers the most realistic hope to date for inexpensive, accessible, and effective prevention of a common invasive secondary infection in patients with HIV-1 disease in Africa. This study establishes the feasibility of successfully performing an efficacy trial for prevention of invasive S. pneumoniae infections with pneumococcal vaccine in this high-risk population as well as for identifying potential mechanisms for vaccine failure (e.g., poor immunogenicity or inappropriate selection of serotypes).
We thank Dr Robert Austrian (University of Pennsylvania, USA) for performing serotyping of pneumococcal isolates, Ann Emery for manuscript preparation, and especially the dedicated staff and involved clients at TASO Entebbe for their support and care of the study and study team.
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Keywords:© 1998 Lippincott Williams & Wilkins, Inc.
Vaccination; bacterial disease; Streptococcus pneumoniae; prevention; bacteremia