Aging and infectious diseases: workshop on HIV infection and aging: what is known and future research directions.

Highly active antiretroviral treatment has resulted in dramatically increased life expectancy among patients with HIV infection who are now aging while receiving treatment and are at risk of developing chronic diseases associated with advanced age. Similarities between aging and the courses of human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome suggest that HIV infection compresses the aging process, perhaps accelerating comorbidities and frailty. In a workshop organized by the Association of Specialty Professors, the Infectious Diseases Society of America, the HIV Medical Association, the National Institute on Aging, and the National Institute on Allergy and Infectious Diseases, researchers in infectious diseases, geriatrics, immunology, and gerontology met to review what is known about HIV infection and aging, to identify research gaps, and to suggest high priority topics for future research. Answers to the questions posed are likely to help prioritize and balance strategies to slow the progression of HIV infection, to address comorbidities and drug toxicity, and to enhance understanding about both HIV infection and aging.

A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection.

BACKGROUND: Acute respiratory tract infections caused by Streptococcus pneumoniae are a leading cause of morbidity and mortality in young children. We evaluated the efficacy of a 9-valent pneumococcal conjugate vaccine in a randomized, double-blind study in Soweto, South Africa. METHODS: At 6, 10, and 14 weeks of age, 19,922 children received the 9-valent pneumococcal polysaccharide vaccine conjugated to a noncatalytic cross-reacting mutant of diphtheria toxin (CRM197), and 19,914 received placebo. All children received Haemophilus influenzae type b conjugate vaccine. Efficacy and safety were analyzed according to the intention-to-treat principle. RESULTS: Among children without human immunodeficiency virus (HIV) infection, the vaccine reduced the incidence of a first episode of invasive pneumococcal disease due to serotypes included in the vaccine by 83 percent (95 percent confidence interval, 39 to 97; 17 cases among controls and 3 among vaccine recipients). Among HIV-infected children, the efficacy was 65 percent (95 percent confidence interval, 24 to 86; 26 and 9 cases, respectively). Among children without HIV infection, the vaccine reduced the incidence of first episodes of radiologically confirmed alveolar consolidation by 20 percent (95 percent confidence interval, 2 to 35; 212 cases in the control group and 169 in the vaccinated group) in the intention-to-treat analysis and by 25 percent (95 percent confidence interval, 4 to 41; 158 and 119 cases, respectively) in the per-protocol analysis (i.e., among fully vaccinated children). The incidence of invasive pneumococcal disease caused by penicillin-resistant strains was reduced by 67 percent (95 percent confidence interval, 19 to 88; 21 cases in the control group and 7 in the vaccinated group), and that caused by strains resistant to trimethoprim-sulfamethoxazole was reduced by 56 percent (95 percent confidence interval, 16 to 78; 32 and 14 cases, respectively). CONCLUSIONS: Vaccination with a 9-valent pneumococcal conjugate vaccine reduced the incidence of radiologically confirmed pneumonia. The vaccine also reduced the incidence of vaccine-serotype and antibiotic-resistant invasive pneumococcal disease among children with and those without HIV infection.

Immunogenicity after one, two or three doses and impact on the antibody response to coadministered antigens of a nonavalent pneumococcal conjugate vaccine in infants of Soweto, South Africa.

BACKGROUND: Children <6 months of age are at increased risk of pneumococcal disease. The early immunogenicity of conjugate vaccines therefore may be important to prevent disease in young children. OBJECTIVES: To determine the immunogenicity of a nonavalent pneumococcal conjugate vaccine after one dose, two doses and three doses and its impact on the antibody response to coadministered antigens. METHODS: A total of 500 infants from Soweto were immunized at 6, 10 and 14 weeks of age with either placebo (n = 250) or 9-valent pneumococcal conjugate vaccine (n = 250) containing serotypes 1, 4, 5, 6B, 9V, 14, 18C, 19F and 23F conjugated to CRM(197) mutant diphtheria protein. Blood was taken for determination of serotype-specific IgG before the first dose and 1 month after each dose. RESULTS: Before the first dose at 6 weeks of age >80% of infants had >0.15 microg/ml antibody to six of the nine antigens, >70% to serotypes 18C and 23F and >50% to serotype 4. Geometric mean concentrations (GMCs) after one dose ranged from 0.27 microg/ml for serotype 23F to 2.98 microg/ml for serotype 1; >90% of infants had serotype-specific antibody >0.15 microg/ml except for serotypes 23F (70%) and 6B (80%). After two doses GMCs ranged from 1.14 microg/ml for serotype 23F to 5.68 microg/ml for serotype 1; >95% of infants had serotype-specific antibody >0.15 microg/ml and >75% had >0.5 microg/ml for all nine serotypes. GMCs after three doses ranged from 2.73 microg/ml for serotype 23F to 6.18 microg/ml for serotype 5; >98% of infants had serotype-specific antibody >0.15 microg/ml and >92% had >0.5 microg/ml for all nine serotypes. Antibody concentrations after three doses were significantly higher to Haemophilus influenzae type b-polyribosylribitol phosphate vaccine in children who received pneumococcal conjugate vaccine, but they had lower antibodies to pertussis toxin than controls. CONCLUSIONS: A single dose of this pneumococcal conjugate vaccine produces a potentially protective antibody response to most serotypes in the majority of children in this population.

Reduced effectiveness of Haemophilus influenzae type b conjugate vaccine in children with a high prevalence of human immunodeficiency virus type 1 infection.

BACKGROUND: Haemophilus influenzae type b (Hib) conjugate vaccines have successfully reduced the burden of invasive Hib disease in developed countries; however, their effectiveness in countries with a high incidence of pediatric HIV-1 is unknown. METHODS: The effectiveness of Hib conjugate vaccine was prospectively evaluated in South African children. The burden of invasive Hib disease in children < 1 year old was compared in 2 cohorts. The first cohort included 22,000 African children born in 1997 [969 (4.45%) of whom were estimated to be HIV-1-infected] who were not vaccinated with Hib conjugate vaccine. This group was compared with 19,267 children [1162 (6.03%) of whom were estimated to be HIV-1 infected] vaccinated at 6, 10 and 14 weeks of age with an Hib conjugate vaccine [TETRAMUNE (polyribosylribitol phosphate-CRM(197)-diphtheria-tetanus toxoids-whole cell pertussis)] between March, 1998, and June, 1999. RESULTS: The estimated burden of invasive Hib disease in nonimmunized HIV-1-infected children < 1 year of age was 5.9-fold [95% confidence interval (95% CI), 2.7 to 12.6] higher than in HIV-1-uninfected children. The overall estimated effectiveness of Hib conjugate vaccine in fully vaccinated children <1 year of age was 83.2% (95% CI 60.3 to 92.9). Vaccine effectiveness was significantly reduced in HIV-1-infected [43.9% (95% CI -76.1 to 82.1)] compared with uninfected children [96.5% (95% CI 74.4 to 99.5); P < 10(-5)]. Among three of the fully vaccinated HIV-1-infected children who developed invasive Hib disease, the anti-Hib polyribosylribitol phosphate serum antibody concentrations were 0.23, 0.25 and 0.68 microg/ml. CONCLUSION: Although the Hib conjugate vaccine was less effective among HIV-1-infected than among uninfected children, it was 83% effective in preventing overall invasive Hib disease and therefore should be considered for inclusion in the routine vaccination schedule by other African countries.

Antibiotic resistance and serotype distribution of Streptococcus pneumoniae colonizing rural Malawian children.

Nasopharyngeal swabs were taken from 906 Malawian children <5 years old visiting rural health clinics. Pneumococcal colonization was high, 84% among all children, and occurred early, 65% of it in children <3 months old. Among pneumococcal isolates 46% were nonsusceptible to trimethoprim-sulfamethoxazole, and 21% were nonsusceptible to penicillin. Trimethoprim-sulfamethoxazole use in the previous month was a risk factor for trimethoprim-sulfamethoxazole and penicillin nonsusceptibility. Forty-three percent of isolates were serotypes included in the 7-valent pneumococcal conjugate vaccine, and 37% were vaccine-related serotypes, particularly 6A and 19A.

Bacterial aetiology of non-resolving otitis media in South African children.

Little is known of the aetiology, serotypes or susceptibility of the pathogens causing non-resolving otitis media in children receiving care from specialists in private practice in developed or in developing countries. Increased access to antibiotics in the community amongst children receiving such private care in South Africa may be anticipated to lead to levels of resistance similar to those found in countries with similar models of private practice, such as the United States. This study was conducted to determine the aetiology of non-resolving otitis media in South African children receiving private care and to determine the antimicrobial resistance patterns and serotypes of the bacterial isolates. Middle-ear fluid was cultured from 173 children aged two months to seven years with non-resolving acute otitis media accompanied by persistent pain or fever who were referred to otorhinolaryngologists for drainage of middle-ear fluid within 14 days of the start of symptoms. While 92 per cent of the children had recently received antibiotics and 54 per cent were currently receiving them, bacteria were isolated from 47 children (27 per cent). Streptococcus pneumoniae was the most common pathogen (35), followed by Haemophilus influenzae (nine), Staphylococcus aureus (six), Moraxella catarrhalis (two), Streptococcus pyogenes (two) and Pseudomonas aeruginosa (one). Two isolates were identified in each of eight children. Antimicrobial resistance to one or more antibiotics was found in 33/35 (94 per cent) of the pneumococci isolated, with resistance to penicillin in 86 per cent, resistance to trimethoprim-sulfamethoxazole in 54 per cent and to erythromycin and clindamycin in 69 per cent and 57 per cent, respectively. The pneumococcal serotypes found were 19F (28 per cent), 14 (26 per cent), 23F (23 per cent), 6B (nine per cent), 19A (87 per cent), and four (three per cent). Children with a bacterial pathogen isolated were younger (mean age of 17 months) than children from whom no bacteria were isolated (mean age of 23 months; p = 0.03). Isolation of a pneumococcus was also significantly associated with younger age (mean = 16 months versus 22 months, p = 0.03), the presence of fever (OR = 2.15, p = 0.049), and having one or more prior episodes of otitis media within the six months before tympanocentesis (OR = 7.72, p = 0.03). Almost all pneumococci isolated from non-resolving acute otitis media in this community are antibiotic-resistant and should be considered especially in young children who have failed previous therapy and who have non-resolving pain or fever.

Apnea and its possible relationship to immunization in ex-premature infants.

This study compared the characteristics of infants hospitalized with apnea that participated in a vaccine trial compared with two control groups which consisted of 100 infants randomly selected from the same vaccine trial and 52 consecutively born very low birth weight (VLBW) infants. A total of 23 infants were admitted with apnea of whom 19 weighed <1500 g at birth and all were born at <37 weeks gestation. More of the VLBW infants in the apnea group had neonatal neurological complications compared with the VLBW control group (p=0.005). Ten of 11 children with apnea within 72 h of immunization were possibly related to vaccination.

Long-term antibody levels and booster responses in South African children immunized with nonavalent pneumococcal conjugate vaccine.

Children who had initially received three doses of either a nonavalent pneumococcal conjugate vaccine containing serotypes 1, 4, 5, 6B, 9V, 14, 18C, 19F, and 23F or placebo at 6, 10, and 14 weeks of age were bled at 9 and 18 months for determination of antibody concentrations. The children were then randomized to receive a booster dose of either the 9-valent pneumococcal conjugate vaccine or a 23-valent polysaccharide vaccine and antibody levels determined 1 month later. At 9 months, the geometric mean concentrations (GMCs) were significantly higher for all vaccine serotypes in vaccinated children compared with controls (means varied from 0.49 microg/ml for serotype 4 to 2.37 microg/ml for serotype 14). At 18 months, antibody concentrations remained significantly higher in vaccinated children (means varied from 0.19 microg/ml for serotype 4 to 1.1 microg/ml for serotype 14). In children who had received conjugate vaccine in infancy, the conjugate vaccine at 18 months produced a significant booster response for serotypes 1, 6B, 14, 19F, and 23F (means varied from 2.74 microg/ml for serotype 19F to 15.52 microg/ml for serotype 6B) and produced a comparable response to a first dose of conjugate at this age for serotypes 4, 5, 9V, and 18C. Boosting at 18 months with polysaccharide vaccine produced higher antibody concentrations to all serotypes in children who had previously received conjugate vaccine compared to children who had not received the conjugate vaccine in infancy. In conclusion, the 9-valent pneumococcal conjugate vaccine given in infancy elicits significant and long-lasting antibody responses which can be boosted with either the conjugate or polysaccharide vaccines.

Dose response of CRM197 and tetanus toxoid-conjugated Haemophilus influenzae type b vaccines.

High vaccine cost has limited use of conjugate vaccines in the developing world where the disease burden is greatest. Fixed fractional doses of Haemophilus influenzae type b (Hib) vaccines have been shown to be immunogenic, but dose responses of these vaccines in humans are needed to determine the lowest immunogenic dose as an option for lowering vaccine cost. We randomized children to receive one of five doses (0.625, 1.25, 2.5, 5.0 and 10 microg) of either a diphtheria CRM197 or tetanus toxoid-conjugated Hib vaccine. The children received a primary three-dose series at 6, 10, and 14 weeks of age and a booster dose at 9 months. Anti-PRP IgG antibodies were measured at each vaccination, at 18 weeks, and at one week following the booster dose. Concentrations of > or =1.25 microg of HibCRM197 vaccine produced mean anti-PRP responses at 18 weeks of > or =5.72 microg/ml and > or =0.15 microg/ml was achieved in >98% of the children with at least 79% reaching anti-PRP concentrations of > or =1.0 microg/ml. Concentrations of > or =1.25 microg of Hib-tetanus vaccine produced mean anti-PRP responses at 18 weeks of > or =8.63 microg/ml and > or =0.15 microg/ml was achieved in 100% of the children with at least 88.9% reaching anti-PRP concentrations of > or =1.0 microg/ml. While mean antibody concentrations after either vaccine decreased over time, the proportion of children with antibody levels of > or =0.15 microg/ml had not changed significantly at the 9 month measurement. Immunologic memory was demonstrated by significant increases in mean antibody concentrations one week after the booster dose for doses > or =1.25 microg of HibCRM197 and Hib-tetanus to mean concentrations > or =37.71 and 16.07 microg/ml, respectively. There were no differences in antibody responses for vaccine doses > or =1.25 microg of the same vaccine or between the same concentrations of the two different vaccines. Our data suggest that doses of these vaccines of > or =1.25 microg may be sufficient to stimulate an immune response that offers both short and longer term protection from invasive Hib disease.