Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in The Gambia: randomised, double-blind, placebo-controlled trial.

BACKGROUND: Pneumonia is estimated to cause 2 million deaths every year in children. Streptococcus pneumoniae is the most important cause of severe pneumonia. We aimed to assess the efficacy of a nine-valent pneumococcal conjugate vaccine in children. METHODS: We undertook a randomised, placebo-controlled, double-blind trial in eastern Gambia. Children age 6-51 weeks were randomly allocated three doses of either pneumococcal conjugate vaccine (n=8718) or placebo (8719), with intervals of at least 25 days between doses. Our primary outcome was first episode of radiological pneumonia. Secondary endpoints were clinical or severe clinical pneumonia, invasive pneumococcal disease, and all-cause admissions. Analyses were per protocol and intention to treat. FINDINGS: 529 children assigned vaccine and 568 allocated placebo were not included in the per-protocol analysis. Results of per-protocol and intention-to-treat analyses were similar. By per-protocol analysis, 333 of 8189 children given vaccine had an episode of radiological pneumonia compared with 513 of 8151 who received placebo. Pneumococcal vaccine efficacy was 37% (95% CI 27-45) against first episode of radiological pneumonia. First episodes of clinical pneumonia were reduced overall by 7% (95% CI 1-12). Efficacy of the conjugate vaccine was 77% (51-90) against invasive pneumococcal disease caused by vaccine serotypes, 50% (21-69) against disease caused by all serotypes, and 15% (7-21) against all-cause admissions. We also found an efficacy of 16% (3-28) against mortality. 110 serious adverse events arose in children given the pneumococcal vaccine compared with 131 in those who received placebo. INTERPRETATION: In this rural African setting, pneumococcal conjugate vaccine has high efficacy against radiological pneumonia and invasive pneumococcal disease, and can substantially reduce admissions and improve child survival. Pneumococcal conjugate vaccines should be made available to African infants.

Immunogenicity and efficacy of childhood vaccines in HIV-1-infected children.

Children infected by HIV-1 are particularly vulnerable to severe, recurrent, or unusual infections by vaccine-preventable pathogens. Routine immunisations seem to be generally safe for HIV-1-infected children, but responses may be suboptimal. Early HIV-1-induced immune attrition associated with viral replication may particularly interfere with the development of memory responses. In high HIV-1 prevalence regions, the accumulation of susceptible hosts may compromise disease-control efforts. Although early control of viral replication through treatment with highly active therapy may preserve immune function and responses to routine childhood vaccines, availability is limited in the areas most affected. In this review, we provide an overview of the immunogenicity and efficacy of childhood vaccines in HIV-1-infected children. The possible immunological bases for defective responses are discussed; unanswered questions and the need for further research are delineated.

Vaccines for children: policies, politics and poverty.

The dawn of the 21st century ushered in spectacular advances in vaccine production technology. However, the benefits of these developments have been largely confined to the world's most affluent and least afflicted. Of the 14 million deaths that occur world-wide in children aged less than 5 years, over 95% of these occur in developing countries and at least 70% are caused by infections for which vaccines are already available in other countries. While impoverished countries do not have a right to be assisted with the provision of funds or vaccines by affluent developed countries, an initiative for the global eradication of a vaccine preventable disease, requires a global effort. Assisting developing countries to achieve such goals should be a high priority for wealthy nations, even if only to protect their own populations. With improved international travel, not only can newly emerging diseases spread across the globe, but pathogens eliminated from one population can be re-imported by travellers or immigrants. In contrast, the recent decline in acceptance of immunisation programmes in developed countries are secondary to strong anti-vaccine movements attributing unproven adverse reactions to vaccines, placing these life-saving vaccines into disrepute. A fertile ground for propagation of these ideologies is created by parents who in their lifetime may not have seen a child killed or maimed from bacterial meningitis or measles and therefore have little understanding of the risk-benefit of vaccination. The development and deployment of vaccines must be a global effort as are the treaties for global disarmament for weapons of mass destruction.

The new pneumococcal vaccine.

Pneumococcal disease is now the leading cause of vaccine-preventable bacterial disease in children worldwide. Although a pneumococcal polysaccharide vaccine has been available for over three decades, its use has been limited due to poor immunogenicity in the most vulnerable children, aged less than 2 years. The prevalence of pneumococcal disease worldwide and the alarming global escalation of multiresistant strains of Streptococcus pneumoniae (pneumococcus) during the past decade have provided the impetus for the development and application of a new pneumococcal vaccine. The outstanding success of Haemophilus influenzae type b (Hib) conjugate vaccine in the control of invasive Hib disease is a reason to be optimistic that the pneumococcal conjugate vaccines will achieve similar results for the control of invasive pneumococcal disease. Remarkable efficacy against invasive pneumococcal disease with a seven-valent pneumococcal conjugate vaccine was demonstrated in infants and toddlers in the USA, and in February 2000 the first pneumococcal conjugate vaccine was licensed. Licensure and widespread use is likely to follow in other countries in which there is a need and the means to afford this live-saving vaccine. Active disease surveillance must be sustained globally, while active research, development of other multivalent conjugate formulations and the search for new candidate protein-based vaccines are in progress.

Evaluation of Binax now Streptococcus pneumoniae urinary antigen test in children in a community with a high carriage rate of pneumococcus.

Pneumococcal antigen was present in urine from 49 of 102 well Gambian children. Eighty-nine of the 102 were nasopharyngeal carriers of pneumococci. The positive predictive value for carriage was 96%, and the negative predictive value was 22%. The test is not useful for predicting etiology of disease in populations with a high rate of nasopharyngeal carriage of pneumococci.

Electrolyte derangement in cerebral malaria: a case for a more aggressive approach to the management of hyponatraemia.

Although hyponatraemia has been consistently shown to occur in a large proportion of children with cerebral malaria, no statistical relationship has been established between the incidence of hyponatraemia and that of malaria-attributable mortality. However, hyponatraemia is not a benign state in other conditions (such as meningitis) or in surgical patients, and is likely to add to malarial deaths. The high mortality rate seen among cases of cerebral malaria, despite all efforts to curb it, therefore calls for a more aggressive approach to the management of hyponatraemia. Current methods for the administration of hypotonic saline and isotonic glucose solutions need review. In addition, children admitted with cerebral malaria should have their electrolyte status monitored to identify new or ongoing hyponatraemia. When hyponatraemia is discovered, it should be quickly and actively corrected.

Diagnosis of childhood pneumonia in the tropics.

Recent global estimates indicate that there are 10 million deaths annually of children aged < 5 years and that 99% of these deaths occur in developing countries, with 70% caused by infections. Pneumonia is the leading cause of the infection-attributable mortality in this age-group, accounting for > 2 million of the deaths. These deaths are potentially preventable if appropriate clinical and laboratory tools are in place to facilitate early detection of the pneumonia, identification of the pathogen involved, and institution of appropriate therapy or, even better, implementation of appropriate vaccination schedules. The currently available tools for the diagnosis of acute, lower-respiratory-tract infections in children have low sensitivity and are, in any case, grossly underutilized. Consequently, there is a great shortage of the data necessary for implementing potentially effective, intervention measures. This review is of the common aetiological agents of childhood pneumonia in the tropics and of the clinical and laboratory techniques currently available for routine diagnosis. Although there are newer and more sensitive diagnostic tools, they are expensive and are not likely to be within reach of most developing countries in the tropics. There is, however, considerable scope to improve the use of the cheaper techniques, and so facilitate the development and implementation of effective control measures.

Safety and immunogenicity of a nonavalent pneumococcal vaccine conjugated to CRM197 administered simultaneously but in a separate syringe with diphtheria, tetanus and pertussis vaccines in Gambian infants.

BACKGROUND: Unrelenting high morbidity and mortality have mandated that immunogenic vaccines be used to combat pneumococcal disease in infants. OBJECTIVES: To evaluate the safety and immunogenicity of a nonavalent pneumococcal conjugate vaccine and the antigenic interaction when administered simultaneously with diphtheria, tetanus and pertussis vaccines. METHODS: Two hundred seven infants were randomized to receive three doses of either nonavalent protein conjugate pneumococcal vaccine (PnCV) or inactivated polio vaccine (IPV) at 2, 3 and 4 months of age with routine Expanded Program of Immunization vaccines as scheduled. Vaccinees were visited on Days 1, 2 and 7 to observe local and systemic adverse reactions. Blood was drawn before the first dose and 1 month after the third dose. Antibody concentrations in sera were measured by standardized enzyme-linked immunosorbent assay. Nasopharyngeal carriage of pneumococci was tested at 5 and 9 months of age. RESULTS: No serious reactions were observed. Local induration and tenderness were observed more commonly at the site of administration of diphtheria, tetanus and pertussis vaccines than at the site of administration of IPV or PnCV. Between 79 and 91% achieved >1 microg/ml antibody against specific pneumococcal serotypes. Antibody responses to diphtheria and pertussis antigens were similar in both groups; however, antibody response to tetanus toxoid was significantly lower in infants who received PnCV (geometric mean concentration, 11.1 vs. 17.4; P < 0.001). Nasopharyngeal carriage in PnCV-vaccinated children was reduced but not significantly different from those vaccinated with IPV. CONCLUSION: Simultaneous administration of PnCV with Expanded Program of Immunization vaccines is safe and immunogenic. immune response to the composite antigens is likely to confer protection.

Prospects for pneumococcal vaccination in African children.

Streptococcus pneumoniae (pneumococcus) remains a major cause of morbidity and mortality in both developed and undeveloped countries. Accurate disease burden estimates for developing countries and Africa in particular, where diagnostic facilities are less adequate and a disease surveillance system virtually non-existent, is difficult. However, from conservative estimates, the pneumococcus is probably responsible for at least 1 million of the 4 million deaths that occur from acute lower respiratory infections in children aged less than 5 years. The global burden of disease has been accentuated by the rising menace of multi-drug resistant strains, which defy geographic and racial borders. Thus, now more than ever before, there is an urgent need to identify and implement preventive measures to avert this problem. The currently licensed pneumococcal polysaccharide vaccine, comprises 23 capsular polysaccharides of the pneumococcus, many of which are poorly immunogenic in the very vulnerable age group of under-fives. A possible solution to the problem of poor immunogenicity is to use a protein/polysaccharide conjugate vaccine similar to that recently introduced successfully for Haemophilus influenzae type b (Hib) and using this approach, several workers have reported promising results from safety and immunogenicity studies. However, unlike Hib, the development of conjugate vaccine against pneumococcal disease is complicated by the existence of more serotypes than can be feasibly incorporated in a single conjugate vaccine formulation. Whilst this challenge has been taken on by some vaccine manufacturers, novel approaches such as the identification or construction of protective protein antigen, common to all clinically important strains are being explored. Novel application of the pneumococcal polysaccharide vaccines in pregnancy for protection of disease in early infancy is an approach that has not been evaluated. For maximum impact, the ultimate vaccine formulation should be affordable and available to resource poor countries where the burden of disease is highest. Establishing disease surveillance systems in such countries now will greatly facilitate the introduction of the vaccines.

Confronting the pneumococcus: a target shift or bullet change?

Pneumococcal disease remains a major killer, despite several years of biomedical research and vaccine technology. The striking efficacy of a seven-valent pneumococcal conjugate vaccine in the US brings hope for the potential conquest of pneumococcal disease but there are still several obstacles in completing this conquest. Although capsular specific antibodies have been shown to be highly protective, it remains unclear what concentration of these serotype-specific antibodies protect against disease and more recently it has become clear that opsonic activity and avidity of these antibodies are more critical determinants of protection than concentration. During the last decade the immunogenicity and protective capacity of several pneumococcal proteins have been described in animal models and these are now being explored for the development of species-common protein based vaccines. Protein conjugate vaccines are no doubt a great new addition to our amarmatorium in the battle against pneumococcal disease but for several epidemiologic reasons the results from Northern California will not be applicable to most other parts of the world. The vaccine contains a limited number of pneumococcal serotypes and given adequate ecological pressure, replacement disease by non-vaccine serotypes remains a real threat, particularly in areas with very high disease burden. The development of new non-serotype-specific vaccine candidates should be encouraged. Defining immune correlates of protection is crucial for the evaluation of these new generation vaccines. As currently available diagnostic methods are poorly sensitive, the true burden of pneumococcal disease may not be revealed until there is a highly efficacious vaccine in widespread use.

The host response in malaria and depression of defence against tuberculosis.

Malaria causes significant morbidity and mortality world-wide. Both asymptomatic and symptomatic malarial infections cause immune depression, which predisposes the host to infection with other microorganisms. Specific clinical investigations have shown, for example, that those with malaria-attributable anaemia are particularly likely to have Salmonella septicaemia, and that asymptomatic malarial infection causes diminished response to polysaccharide vaccine. The results of clinical studies and experiments with animal models have revealed that malarial parasites can decrease their vertebrate host's effective humoral and cellular immune responses. In this review, the possible ways in which this malaria-induced immune impairment could affect the host's response to Mycobacterium tuberculosis infection are considered. Could malarial infection be one of the reasons for the persistence of tuberculosis in malaria-endemic regions?

A trial of Fansidar plus chloroquine or Fansidar alone for the treatment of uncomplicated malaria in Gambian children.

Chloroquine can no longer be recommended as the first-line treatment for uncomplicated malaria in several parts of Africa because of the increasing prevalence of chloroquine resistance. However, chloroquine was a highly effective treatment for malaria not only because of its ability to kill parasites quickly but also because it is an anti-inflammatory drug. Therefore, we have investigated whether Fansidar (pyrimethamine/sulfadoxine) plus chloroquine is a more effective treatment for uncomplicated malaria than Fansidar alone. Four hundred and five Gambian children with uncomplicated Plasmodium falciparum malaria were studied in a randomized controlled trial. Significantly more children treated with Fansidar alone, compared to those treated with Fansidar plus chloroquine (19/203 vs. 2/202; P < 0.001), returned to the clinic with persistent symptoms during the first 3 d after treatment. Three children who had received Fansidar alone had fits, but none of the children treated with Fansidar plus chloroquine did so. At the day 7 follow-up, the parasite failure rate in the Fansidar alone group was 3/198 (1.5%), whilst in the Fansidar plus chloroquine group it was 3/201 (1.5%). At the day 28 follow-up, there was still no significant difference between the parasite failure rate in the Fansidar alone group (15/150; 10.0%) and the Fansidar plus chloroquine group (7/141; 5.0%) and the mean packed cell volume (PCV) in the 2 groups was similar. Thus, a combination of Fansidar plus chloroquine was a more effective symptomatic treatment than Fansidar given alone, but neither the parasite cure rate nor the PCV was enhanced by use of the combination.

An efficacy trial of the malaria vaccine SPf66 in Gambian infants--second year of follow-up.

In 1994, 630 Gambian infants were immunized with three doses of the synthetic polypeptide malaria vaccine SPf66 or with a control vaccine. No significant protection against first or total attacks of malaria was observed among the children who received SPf66. However, the period of follow-up was short. Thus, 532 children were followed for a second malaria transmission season during which 291 episodes of malaria were detected. Protective efficacies of SPf66 against first attacks of malaria and against all attacks of malaria were 8% [95% CI-20%, 30%] and 2% [95% CI-26% 24%] respectively. SPf66 did not provide any significant degree of protection to Gambian infants during a second year of follow-up.

Follow-up of Gambian children recruited to a pilot safety and immunogenicity study of the malaria vaccine SPf66.

A pilot safety and immunogenicity trial of the malaria vaccine SPf66 was undertaken in The Gambia in 1993. One hundred and fifty infants aged 6-11 months were immunized with either 0.5 mg or 1.0 mg of SPf66 produced either in Colombia or in the USA or with a control vaccine. Children who received SPf66 experienced more clinical attacks of malaria than did children in the control group during the first period of surveillance and the difference in incidence between children who had received high dose Colombian vaccine and the control children was statistically significant at the 5% level. During the 1995 malaria transmission season, 127 children from the original cohort of 150 were observed. During 18 weeks of intensive surveillance, the incidence of clinical malaria was again higher among children who had received SPf66 than among children who had received inactivated polio vaccine (6.23 vs 4.89 clinical attacks per 1000 days at risk), the effect being most marked among children who were in the high dose groups, but differences between groups were now no longer statistically significant.

PIP: 150 human subjects aged 6-11 months were involved in a pilot safety and immunogenicity trial of the malaria vaccine SPf66 conducted in The Gambia in 1993. The infants were immunized with either 0.5 mg or 1.0 mg of the vaccine produced in either Colombia or the US, or with a control vaccine. Children who received SPf66 experienced more clinical attacks of malaria than did children in the control group during the first period of surveillance, with the difference in incidence between children who had received high dose Colombian vaccine and the control children being statistically significant. 127 children from the original cohort of 150 were observed during the 1995 malaria transmission season. During 18 weeks of intensive surveillance, the incidence of clinical malaria was again higher among children who had received SPf66 than among children who had received inactivated polio vaccine. The effect was most marked among children in the high dose groups, although the intergroup differences were statistically insignificant. The SPf66 vaccine may have induced an immune response which made the immunized children more susceptible to malaria. It is also possible that the increased susceptibility to malaria among children who received SPf66 was a chance event following the randomization process. No enhancement of either disease frequency or severity was found in a much larger efficacy trial of Colombian SPf66 conducted among Gambian children during a 2-year follow-up period.

A glycoprotein pneumococcal conjugate vaccine primes for antibody responses to a pneumococcal polysaccharide vaccine in Gambian children.

BACKGROUND: Streptococcus pneumoniae is a major cause of acute respiratory infections and acute bacterial meningitis in children. Pneumococcal polysaccharide vaccines are poorly immunogenic in this highly vulnerable group, but protein polysaccharide conjugate vaccines are likely to be more effective. OBJECTIVES: To determine whether immunization of infants with a pneumococcal conjugate vaccine induces immunologic memory. METHODS: Eighty-four Gambian children, who had been vaccinated previously with two or three doses of a pentavalent pneumococcal conjugate vaccine (CRM197) or with a Haemophilus influenzae type b (Hib) conjugate vaccine were immunized when approximately 2 years old with a 23-valent pneumococcal polysaccharide vaccine, and a blood sample was obtained 10 days later. Pneumococcal antibody titers in prevaccination and postvaccination sera were measured by enzyme-linked immunosorbent assay and by an opsonophagocytic assay. RESULTS: On revaccination with a pneumococcal polysaccharide vaccine, children who had previously received pneumococcal conjugate vaccine had higher antibody concentrations to each of the five polysaccharide components of the conjugate vaccine than did control children. For type 6B polysaccharide, which is poorly immunogenic in young children, postvaccination antibody concentrations were 0.37, 27.6 and 50.9 microg/ml in children who had received no previous pneumococcal immunization or two or three doses of conjugate vaccine, respectively. Type 14 antibodies produced after revaccination were of high avidity and had opsonic activity. CONCLUSION: Vaccination of young infants with two or three doses of a pneumococcal conjugate vaccine primes the immune system to respond strongly and rapidly on subsequent exposure to pneumococcal polysaccharide.