Four year immunogenicity of the RTS,S/AS02(A) malaria vaccine in Mozambican children during a phase IIb trial

Previous studies with the malaria vaccine RTS,S/AS02_A in young children in a malaria endemic area of Mozambique have shown it to have a promising safety profile and to reduce the risk of Plasmodium falciparum infection and disease.In this study, we assessed the antibody responses to the P. falciparum and hepatitis B components of the RTS,S/AS02_A vaccine over a 45 months surveillance period in a large phase IIb trial which included 2022 children aged 1-4 years at recruitment.The RTS,S/AS02_A vaccine induced high anti-circumsporozoite antibody levels with at least 96% of children remaining seropositive during the entire follow-up period. IgG titers decayed over the first 6 months of follow-up to about 25% of the initial level, but still remained 30-fold higher until month 45 compared to controls. Children with higher levels of naturally acquired immunity at baseline, assessed by blood stage indirect fluorescent antibody test, had slightly higher anti-circumsporozoite levels, after adjusting for the effect of age.The RTS,S/AS02_A vaccine also induced high levels of anti-hepatitis B surface antigen antibodies (seroprotection >97%).RTS,S/AS02_A vaccine is immunogenic and induces long-lasting anti-circumsporozoite antibodies, persisting at least 42 months after immunization. These antibodies may play a role in protection against malaria.     

Evaluation of the safety and immunogenicity of Plasmodium falciparum apical membrane antigen 1, merozoite surface protein 1 or RTS,S vaccines with adjuvant system AS02A administered alone or concurrently in rhesus monkeys

In an effort to broaden the immune response induced by the RTS,S/AS02_A,vaccine, we have evaluated the immunogenicity of the RTS,S antigen when combined with MSP1₄₂ and with AMA1, antigens derived from the asexual blood stage. The objectives of this study were (i) to determine whether MSP1₄₂ and AMA1 vaccines formulated with the AS02_A Adjuvant System were safe and immunogenic in the rhesus monkey model; (ii) to investigate whether MSP1₄₂ or AMA1 induced immune interference to each other, or to RTS,S, when added singly or in combinations at a single injection site; (iii) in the event of immune interference, to determine if this could be reduced when antigens were administered at separate sites. We found that MSP1₄₂ and AMA1 were safe and immunogenic, eliciting antibodies, and Th1 and Th2 responses using IFN-γ and IL-5 as markers. When malaria antigens were delivered together in one formulation, MSP1₄₂ and RTS,S reduced AMA1-specific antibody responses as measured by ELISA however, only MSP1₄₂ lowered parasite growth inhibitory activity of anti-AMA1 antibodies as measured by in vitro growth inhibition assay. Unlike RTS,S, MSP1₄₂ significantly reduced AMA1 IFN-γ and IL-5 responses. MSP1₄₂ suppression of AMA1 IFN-γ responses was not seen in animals receiving RTS,S + AMA1 + MSP1₄₂ suggesting that RTS,S restored IFN-γ responses. Conversely, AMA1 had no effect on MSP1₄₂ antibody and IFN-γ and IL-5 responses. Neither AMA1 alone or combined with MSP1₄₂ affected RTS,S antibody or IFN-γ and IL-5 responses. Immune interference by MSP1₄₂ on AMA1 antibody responses was also evident when AMA1, MSP1₄₂ and RTS,S were administered concurrently at separate sites. These results suggest that immune interference may be complex and should be considered for the design of multi-antigen, multi-stage vaccines against malaria.     

RTS,S/AS01E malaria vaccine induces IgA responses against CSP and vaccine-unrelated antigens in African children in the phase 3 trial

BackgroundThe evaluation of immune responses to RTS,S/AS01 has traditionally focused on immunoglobulin (Ig) G antibodies that are only moderately associated with protection. The role of other antibody isotypes that could also contribute to vaccine efficacy remains unclear. Here we investigated whether RTS,S/AS01_E elicits antigen-specific serum IgA antibodies to the vaccine and other malaria antigens, and we explored their association with protection.MethodsNinety-five children (age 5–17 months old at first vaccination) from the RTS,S/AS01_E phase 3 clinical trial who received 3 doses of RTS,S/AS01_E or a comparator vaccine were selected for IgA quantification 1 month post primary immunization. Two sites with different malaria transmission intensities (MTI) and clinical malaria cases and controls, were included. Measurements of IgA against different constructs of the circumsporozoite protein (CSP) vaccine antigen and 16 vaccine-unrelated Plasmodium falciparum antigens were performed using a quantitative suspension array assay.ResultsRTS,S vaccination induced a 1.2 to 2-fold increase in levels of serum/plasma IgA antibodies to all CSP constructs, which was not observed upon immunization with a comparator vaccine. The IgA response against 13 out of 16 vaccine-unrelated P. falciparum antigens also increased after vaccination, and levels were higher in recipients of RTS,S than in comparators. IgA levels to malaria antigens before vaccination were more elevated in the high MTI than the low MTI site. No statistically significant association of IgA with protection was found in exploratory analyses.ConclusionsRTS,S/AS01_E induces IgA responses in peripheral blood against CSP vaccine antigens and other P. falciparum vaccine-unrelated antigens, similar to what we previously showed for IgG responses. Collectively, data warrant further investigation of the potential contribution of vaccine-induced IgA responses to efficacy and any possible interplay, either synergistic or antagonistic, with protective IgG, as identifying mediators of protection by RTS,S/AS01_E immunization is necessary for the design of improved second-generation vaccines.Clinical trial registration: ClinicalTrials.gov: NCT008666191.     

Country specific predictions of the cost-effectiveness of malaria vaccine RTS,S/AS01 in endemic Africa

BackgroundRTS,S/AS01 is a safe and moderately efficacious vaccine considered for implementation in endemic Africa. Model predictions of impact and cost-effectiveness of this new intervention could aid in country adoption decisions.MethodsThe impact of RTS,S was assessed in 43 countries using an ensemble of models of Plasmodium falciparum epidemiology. Informed by the 32 months follow-up data from the phase 3 trial, vaccine effectiveness was evaluated at country levels of malaria parasite prevalence, coverage of control interventions and immunization. Benefits and costs of the program incremental to routine malaria control were evaluated for a four dose schedule: first dose administered at six months, second and third - before 9 months, and fourth dose at 27 months of age. Sensitivity analyses around vaccine properties, transmission, and economic inputs were conducted.ResultsIf implemented in all 43 countries the vaccine has the potential to avert 123 (117; 129) million malaria episodes over the first 10 years. Burden averted averages 18,413 (range of country median estimates 156–40,054) DALYs per 100,000 fully vaccinated children with much variation across settings primarily driven by differences in transmission intensity. At a price of $5 per dose program costs average $39.8 per fully vaccinated child with a median cost-effectiveness ratio of $188 (range $78–$22,448) per DALY averted; the ratio is lower by one third - $136 (range $116–$220) - in settings where parasite prevalence in children aged 2–10 years is at or above 10%.ConclusionRTS,S/AS01 has the potential to substantially reduce malaria burden in children across Africa. Conditional on assumptions on price, coverage, and vaccine properties, adding RTS,S to routine malaria control interventions would be highly cost-effective. Implementation decisions will need to further consider feasibility of scaling up existing control programs, and operational constraints in reaching children at risk with the schedule.     

RTS,S malaria vaccine efficacy and immunogenicity during Plasmodium falciparum challenge is associated with HLA genotype

Although RTS,S remains the most advanced malaria vaccine, the factors influencing differences in vaccine immunogenicity or efficacy between individuals or populations are still poorly characterised. The analyses of genetic determinants of immunogenicity have previously been restricted by relatively small sample sizes from individual trials. Here we combine data from six Phase II RTS,S trials and evaluate the relationship between HLA allele groups and RTS,S-mediated protection in controlled human malaria infections (CHMI), using multivariate logistic or linear regression. We observed significant associations between three allele groups (HLA-A¹01, HLA-B¹08, and HLA-DRB1¹15/¹16) and protection, while another three allele groups (HLA-A¹03, HLA-B¹53, and HLA-DRB1¹07) were significantly associated with lack of protection. It is noteworthy that these ‘protective’ allele groups are thought to be at a lower prevalence in sub-Saharan African populations than in the UK or USA where these Phase II trials occurred. Taken together, the analyses presented here give an indication that HLA genotype may influence RTS,S-mediated protective efficacy against malaria infection.     

Plasmodium falciparum serine repeat antigen 5 (SE36) as a malaria vaccine candidate

A devastating disease spread by mosquitoes with high-efficiency, malaria imposes an enormous burden for which no licensed vaccine currently exists. Although the genome complexity of the parasite has made vaccine development tenuous, an effective malaria vaccine would be a valuable tool for control, elimination and eventual eradication. The Plasmodium serine repeat antigen 5 (SERA5) is an abundant asexual blood stage antigen that does not show any antigenic variation and exhibits limited polymorphism, making it a suitable vaccine candidate. Identified by comparing the IgG status of people in endemic areas with protective immunity and those with malaria symptoms, the vaccine potential of the N-terminal domain of Plasmodium falciparum SERA5 is also strongly supported by experimental data and immune responses both measured in vitro and in animal challenge models. The current understanding of SERA5 will be presented, particularly in relation to its path towards clinical development. The review highlights lessons learned and sorts out issues upon which further research efforts are needed.     

Geographic differentiation of polymorphism in the Plasmodium falciparum malaria vaccine candidate gene SERA5

SERA5 is regarded as a promising malaria vaccine candidate of the most virulent human malaria parasite Plasmodium falciparum. SERA5 is a 120 kDa abundantly expressed blood-stage protein containing a papain-like protease. Since substantial polymorphism in blood-stage vaccine candidates may potentially limit their efficacy, it is imperative to fully investigate polymorphism of the SERA5 gene (sera5). In this study, we performed evolutionary and population genetic analysis of sera5. The level of inter-species divergence (kS=0.076) between P. falciparum and Plasmodium reichenowi, a closely related chimpanzee malaria parasite is comparable to that of housekeeping protein genes. A signature of purifying selection was detected in the proenzyme and enzyme domains. Analysis of 445 near full-length P. falciparum sera5 sequences from nine countries in Africa, Southeast Asia, Oceania and South America revealed extensive variations in the number of octamer repeat (OR) and serine repeat (SR) regions as well as substantial level of single nucleotide polymorphism (SNP) in non-repeat regions (2562 bp). Remarkably, a 14 amino acid sequence of SERA5 (amino acids 59-72) that is known to be the in vitro target of parasite growth inhibitory antibodies was found to be perfectly conserved in all 445 worldwide isolates of P. falciparum evaluated. Unlike other major vaccine target antigen genes such as merozoite surface protein-1, apical membrane antigen-1 or circumsporozoite protein, no strong evidence for positive selection was detected for SNPs in the non-repeat regions of sera5. A biased geographical distribution was observed in SNPs as well as in the haplotypes of the sera5 OR and SR regions. In Africa, OR- and SR-haplotypes with low frequency (<5%) and SNPs with minor allele frequency (<5%) were abundant and were mostly continent-specific. Consistently, significant genetic differentiation, assessed by the Wright's fixation index (Fst) of inter-population variance in allele frequencies, was detected for SNPs and both OR- and SR-haplotypes among almost all parasite populations. The exception was parasite populations between Tanzania and Ghana, suggesting frequent gene flow in Africa. The present study points to the importance of investigating whether biased geographical distribution for SNPs and repeat variants in the OR and SR regions affect the reactivity of human serum antibodies to variants.     

Randomized double-blind controlled Phase I/IIa trial to assess the efficacy of malaria vaccine PfCS102 to protect against challenge with P. falciparum

The aim of this Phase I/IIa double-blind controlled trial was to test the efficacy of the sporozoite-based malaria vaccine PfCS 282–383 (PfCS102) to protect against Plasmodium falciparum parasitaemia. 16 volunteers were randomized to receive twice 30 μg of PfCS102 formulated in Montanide ISA 720 or ISA 720 alone (control). Two weeks after 2nd immunization, volunteers were challenged using 5 infected mosquitoes. All vaccinees developed antibodies against PfCS102 versus none control. 8/8 vaccinees and 6/6 controls challenged developed malaria parasitaemia. The duration from infection to onset of patent parasitaemia was similar in both groups (214 h in vaccinees and 216 in controls). PfCS102 is safe and immunogenic but provides no protection against artificial challenge in its current formulation.     

Safety and immunogenicty of RTS,S/AS02A candidate malaria vaccine in Gambian children

RTS,S/AS02A is a pre-erythrocytic malaria vaccine candidate in which a portion of the circumsporozoite surface protein (CSP) of Plasmodium falciparum is genetically linked to hepatitis B surface antigen (HBsAg) coexpressed in yeast with unfused HBsAg. The resulting particulate antigen is formulated with the adjuvant system AS02A. We have initiated the paediatric clinical development of this vaccine by conducting two sequential Phase I studies in children: a study in older children (6--11 years), followed by a second study in younger children (1--5 years). In each study, a double-blind, randomised controlled, staggered, dose-escalation design was used to evaluate 10 microg RTS,S dose (10 microg RTS,S in 0.1mL AS02A), 25 microg dose (25 microg RTS,S in 0.25mL AS02A) and finally a 50 microg dose (50 microg RTS,S in 0.5mL AS02A) of the RTS,S/AS02A candidate malaria vaccine administered according to a 0-, 1- and 3-month vaccination schedule. Safety and reactogenicity were evaluated before moving to a higher dose level. The RTS,S/AS02A vaccine was safe at all dose levels, in both age groups. No serious adverse events related to vaccination were reported. The frequency of local Grade 3 symptoms was low but tended to increase with increasing dose level. Grade 3 general adverse events in the RTS,S/AS02A groups were infrequent and of short duration. The majority of local and general Grade 3 symptoms resolved or decreased in intensity within 48h. The pattern and intensity of reactogenicity seen in these studies are similar to those of previous studies with RTS,S/AS02A. All doses were highly immunogenic for anti-CSP and anti-HBsAg antibodies. The pooled anti-CSP antibody data from the two studies showed that the 25 microg dose and 50 microg dose anti-CSP antibody response were similar at both dose levels. However, the immunogenicity of the 10 microg dose anti-CSP response was significantly lower than that of either the 50 microg or 25 microg dose. The 25 microg dose was selected for future studies of RTS,S/AS02A in paediatric populations.     

Cell-mediated immunity elicited by the blood stage malaria vaccine apical membrane antigen 1 in Malian adults: Results of a Phase I randomized trial

The development of a safe and effective malaria vaccine is impeded by the complexity of the Plasmodium life cycle. A vaccine that elicits both cell-mediated and humoral immune responses might be needed for protection against this multistage parasitic infection. Apical membrane antigen 1 (AMA-1) plays a key role in erythrocytic invasion but is also expressed in sporozoites and in late stage liver schizonts, where it may provide a target of protective cell-mediated immunity (CMI). A Phase 1 trial of a vaccine consisting of recombinant AMA-1 protein and the Adjuvant system AS02A was conducted in 60 Malian adults aged 18–55 years who were randomized to receive either half-dose (25 μg/0.25 ml) or full dose (50 μg/0.5 ml) FMP2.1/AS02A or a control rabies vaccine. Interleukin 5 (IL-5) and interferon-γ (IFN-γ) production as evaluated by ELISpot and lymphocyte proliferation were measured after in vitro AMA-1 stimulation of peripheral blood mononuclear cells (PBMCs) collected on Days 0 and 90. Post-FMP2.1/AS02A immunization mean stimulation indices were significantly elevated as were the number of IL-5 spot forming cells (SFC)/10⁶ PBMC, but no difference was noted in INF-γ production between the AMA-1/AS02A vaccinated group and the rabies group. These results provide evidence that complex immune responses can be induced by this vaccination strategy and add further impetus for the continuing clinical evaluation of this vaccine.     

Safety and efficacy of dihydroartemisinin/piperaquine (Artekin) for the treatment of uncomplicated Plasmodium falciparum malaria in Rwandan children

In Rwanda, amodiaquine+sulfadoxine/pyrimethamine (AQ+SP) is the current first-line treatment for malaria, introduced in 2001 as an interim strategy before the future deployment of an artemisinin-based combination treatment (ACT). Dihydroartemisinin/piperaquine (DHA-PQP) is a new co-formulated and well tolerated ACT increasingly used in Southeast Asia where it has proved to be highly effective against Plasmodium falciparum malaria. We tested the efficacy, safety and tolerability of DHA-PQP in children with uncomplicated P. falciparum malaria. A randomised, open trial was carried out in 2003-2004. Seven hundred and sixty-two children aged 12-59 months with uncomplicated P. falciparum malaria were randomly allocated to one of the following treatments: amodiaquine+artesunate; AQ+SP; or DHA-PQP. Patients were followed-up until Day 28 after treatment. Adverse events and clinical and parasitological outcomes were recorded. Children treated with DHA-PQP or AQ+AS had a significantly higher cure rate compared with those treated with amodiaquine+sulfadoxine/pyrimethamine (95.2% and 92.0% vs. 84.7%, respectively). Parasite clearance was significantly faster in children treated with DHA-PQP and AQ+AS compared with those treated with amodiaquine+sulfadoxine/pyrimethamine. The frequency of adverse events was significantly lower in patients treated with DHA-PQP than in those treated with combinations containing amodiaquine. A 3-day treatment with DHA-PQP proved to be efficacious with a good safety and tolerability profile and could be a good candidate for the next first-line treatment.     

Costing RTS,S introduction in Burkina Faso,Ghana, Kenya,Senegal, Tanzania,and Uganda: A generalizable approach drawing on publicly available data

Recent results from the phase 3 trial of RTS,S/AS01 malaria vaccine show that the vaccine induced partial protection against clinical malaria in infants and children; given the high burden of the disease it is currently considered for use in malaria endemic countries. To inform adoption decisions the paper proposes a generalizable methodology to estimate the cost of vaccine introduction using routinely collected and publicly available data from the cMYP, UNICEF, and WHO-CHOICE. Costing is carried out around a set of generic activities, assumptions, and inputs for delivery of immunization services adapted to a given country and deployment modality to capture among other factors the structure of the EPI program, distribution model, geography, and demographics particular to the setting. The methodology is applied to estimate the cost of RTS,S introduction in Burkina Faso, Ghana, Kenya, Senegal, Tanzania, and Uganda. At an assumed vaccine price of $5 per dose and given our assumptions on coverage and deployment strategy, we estimate total economic program costs for a 6–9 months cohort within $23.11–$28.28 per fully vaccinated child across the 6 countries. Net of procurement, costs at country level are substantial; for instance in Tanzania these could add as much as $4.2 million per year or an additional $2.4 per infant depending on the level of spare capacity in the system. Differences in cost of vaccine introduction across countries are primarily driven by differences in cost of labour. Overall estimates generated with the methodology result in costs within the ranges reported for other new vaccines introduced in SSA and capture multiple sources of heterogeneity in costs across countries. Further validation with data from field trials will support use of the methodology while also serving as a validation for cMYP and WHO-CHOICE as resources for costing health interventions in the region.     

Immunogenicity of the Plasmodium falciparum Pf332-DBL domain in combination with different adjuvants

The Plasmodium falciparum antigen 332 (Pf332) is a conserved blood-stage antigen, which has been suggested to play a role in parasite invasion. In the present study, we have investigated the immunogenicity of the Duffy-binding like (DBL)-domain of the Pf332 molecule in combination with different adjuvants in four animal species. Three of the adjuvants are applicable for human use (Montanide ISA 720, alum and levamisole), whilst Freund's adjuvant served as a positive control adjuvant. Montanide ISA 720 was able to generate a significant and Th2-biased IgG response in BALB/c and C57BL/6 mice. Alum was a strong inducer of a Th2-type immune response only in BALB/c mice, whereas it was a poor adjuvant together with Pf332-DBL in C57BL/6 mice, rabbits and rats. Levamisole did not show any obvious adjuvant effect in any of the immunized animals. Thus in the case with Pf332-DBL, Montanide ISA 720 may be an adjuvant to further explore in the development of a vaccine against malaria.     

Muscle cell injury, haemolysis and dark urine in children with falciparum malaria in Papua New Guinea

During a prospective study of red cell variants and severe malaria in children, a surprising observation was the occurrence of dark urine. Children were grouped according to urine findings: 22 had dark urine that contained a haem protein (Group I), 93 had urine of normal colour that contained a haem protein (Group II) and 236 had normal urine (Group III). To investigate the cause of dark urine, haemolysis and muscle cell injury were assessed. Intravascular haemolysis was greater in Group I than in Groups II and III. However, anaemia was more severe in Group III and is likely to have resulted mainly from extravascular haemolysis. Median plasma myoglobin concentrations were greater in Groups I and II than Group III (P = 0.00060). Plasma myoglobin was greater in children with cerebral malaria, hyperlactataemia and those who died but was not associated with acidosis. Urine myoglobin was greater in Group I than Groups II and III (P = 0.00054). It is likely that both haemoglobin and myoglobin contributed to dark urine. The association between muscle cell injury and coma suggests sequestration of parasitized red cells as a common underlying pathology. In malaria, hyperlactataemia may result directly from breakdown of muscle protein as well as tissue hypoxia.     

Safety of the RTS,S/AS02A malaria vaccine in Mozambican children during a Phase IIb trial

RTS,S/AS02A is a pre-erythrocytic vaccine candidate based on the Plasmodium falciparum circumsporozoite surface antigen and is currently the most advanced malaria vaccine candidate in development. A proof of concept phase IIb trial of the RTS,S/AS02A in Mozambican children aged 1-4 years determined a vaccine efficacy against risk of clinical malaria of 35.3% (95% CI 21.6-46.6; p<0.0001) and against severe malaria of 48.6% (95% CI 12.3-71.0; p=0.02). We evaluated the safety of the RTS,S/AS02A vaccine. 2022 children that received at least one vaccine dose of RTS,S/AS02A or control vaccines were included in the intention to treat safety analysis. Vaccine safety was evaluated using active and passive follow-up. Participants were observed for at least 1h after each dose. Trained field workers visited children at home daily for the next 3 days to record solicited and unsolicited local and general symptoms. Investigators followed-up participants with severe adverse events until month 21. Overall, we recorded 1712 unsolicited adverse events after vaccination, 53% in the intervention and 47% in the control group. Most unsolicited adverse events reported with RTS,S/AS02A were self-limited, and participants recovered without sequelae. Local reactogenicity increased with the number of doses. The proportion of children experiencing serious adverse events was lower in the RTS,S/AS02A recipients compared to the control group (Engerix-Btrade mark or Prevnartrade mark and Hiberixtrade mark). Overall, these results indicate that the RTS,S/AS02A vaccine has a good safety profile and well tolerated when given in three doses to semi-immune children living in malaria-endemic areas.     

Decrease in circulating CD25hiFoxp3+ regulatory T cells following vaccination with the candidate malaria vaccine RTS,S

Regulatory T (Treg) cells have been shown in some cases to limit vaccine-specific immune responses and impact efficacy. Very little is known about the regulatory responses to the leading malaria vaccine candidate, RTS,S. The goal of this study was to begin to characterize the regulatory responses to the RTS,S vaccine. Using multi-parameter flow cytometry, we examined responses in 13 malaria naïve adult volunteers who received 2 doses of RTS,S given eight weeks apart. Five of these volunteers had previously received 3 doses of a candidate DNA-CSP vaccine, with the final dose given approximately one year prior to the first dose of the RTS,S vaccine.We found that the frequency of CD25^hiFoxp3⁺ Treg cells decreased following administration of RTS,S (p = 0.0195), with no differences based on vaccine regimen. There was a concomitant decrease in CTLA-4 expression on CD25^hiFoxp3⁺ Treg cells (p = 0.0093) and PD-1 levels on CD8⁺ T cells (p = 0.0002). Additionally, the frequency of anergic CTLA-4⁺CCR7⁺ T cells decreased following vaccination. An inverse correlation was observed between the frequency of Plasmodium falciparum circumsporozoite protein (PfCSP)-specific IFN-γ and PfCSP-specific IL-10, as well as an inverse correlation between IL-10 induced by Hepatitis B surface antigen, the carrier of RTS,S, and PfCSP-specific IFN-γ, suggesting that immunity against the vaccine backbone could impact vaccine immunogenicity. These results have implications for future malaria vaccine design.     

The IC50 of anti-Pfs25 antibody in membrane-feeding assay varies among species

Plasmodium falciparum surface protein 25 (Pfs25) is a candidate for transmission-blocking vaccines (TBVs). Anti-Pfs25 antibodies block the development of oocysts in membrane-feeding assays and we have shown the activity correlates with antibody titer. In this study, we purified Pfs25-specific IgGs to convert antibody titer to μg/mL and determined the amount of antibody required to inhibit 50% of oocyst development (IC₅₀). The IC₅₀ were, 15.9, 4.2, 41.2, and 85.6 μg/mL for mouse, rabbit, monkey and human, respectively, and the differences among species were significant. Anti-Pfs25 sera from rabbit, monkey and human showed different patterns of competition against 6 mouse monoclonal antibodies, and the avidity of antibodies among four species were also different. These data suggests that information obtained from animal studies which assess efficacy of TBV candidates may be difficult to translate to human immunization.     

Complications and mortality patterns due to Plasmodium falciparum malaria in hospitalized adults and children,Rourkela, Orissa,India

Of 1857 Plasmodium falciparum malaria patients hospitalized from 1995 to 1998, 608 had severe malaria and 83 died. Acute renal failure, jaundice and respiratory distress were common in adults whereas children frequently had severe anaemia. Cerebral malaria occurred equally in adults and children but recovery from coma was quicker in children. Multiple complications caused high mortality in adults.     

Vaccine preventable disease incidence as a complement to vaccine efficacy for setting vaccine policy

Traditionally, vaccines have been evaluated in clinical trials that establish vaccine efficacy (VE) against etiology-confirmed disease outcomes, a measure important for licensure. Yet, VE does not reflect a vaccine's public health impact because it does not account for relative disease incidence. An additional measure that more directly establishes a vaccine's public health value is the vaccine preventable disease incidence (VPDI), which is the incidence of disease preventable by vaccine in a given context. We describe how VE and VPDI can vary, sometimes in inverse directions, across disease outcomes and vaccinated populations. We provide examples of how VPDI can be used to reveal the relative public health impact of vaccines in developing countries, which can be masked by focus on VE alone. We recommend that VPDI be incorporated along with VE into the analytic plans of vaccine trials, as well as decisions by funders, ministries of health, and regulatory authorities.