Variant surface antigens (VSAs) play a critical role in severe malaria pathogenesis. Defining gaps, or "lacunae", in immunity to these Plasmodium falciparum antigens in children with severe malaria would improve our understanding of vulnerability to severe malaria and how protective immunity develops. Using a protein microarray with 179 antigen variants from three VSA families as well as more than 300 variants of three other blood stage P. falciparum antigens, reactivity was measured in sera from Malian children with cerebral malaria or severe malarial anaemia and age-matched controls. Sera from children with severe malaria recognized fewer extracellular PfEMP1 fragments and were less reactive to specific fragments compared to controls. Following recovery from severe malaria, convalescent sera had increased reactivity to certain non-CD36 binding PfEMP1s, but not other malaria antigens. Sera from children with severe malarial anaemia reacted to fewer VSAs than did sera from children with cerebral malaria, and both of these groups had lacunae in their seroreactivity profiles in common with children who had both cerebral malaria and severe malarial anaemia. This microarray-based approach may identify a subset of VSAs that could inform the development of a vaccine to prevent severe disease or a diagnostic test to predict at-risk children.
Rotarix (GlaxoSmithKline), a newly licensed rotavirus vaccine requiring 2 doses, may have the potential to save hundreds of thousands of lives in Africa. Nations such as Malawi, where Rotarix is currently under phase III investigation, may nevertheless face difficult economic choices in considering vaccine adoption.The cost-effectiveness of implementing a Rotarix vaccine program in Malawi was estimated using published estimates of rotavirus burden, vaccine efficacy, and health care utilization and costs.With 49.5% vaccine efficacy, a Rotarix program could avert 2582 deaths annually. With GAVI Alliance cofinancing, adoption of Rotarix would be associated with a cost of $5.07 per disability-adjusted life-year averted. With market pricing, Rotarix would be associated with a base case cost of $74.73 per disability-adjusted life-year averted. Key variables influencing results were vaccine efficacy, under-2 rotavirus mortality, and program cost of administering each dose.Adopting Rotarix would likely be highly cost-effective for Malawi, particularly with GAVI support. This finding holds true across uncertainty ranges for key variables, including efficacy, for which data are becoming available.
Abstract In Bandiagara, Mali, children experience on average two clinical malaria episodes per season. However, even in the same transmission area, the number of uncomplicated symptomatic infections, and their parasitemia, vary dramatically among children. To examine the factors contributing to these variations, we simultaneously characterized the host and parasite gene expression profiles from 136 children with symptomatic falciparum malaria and analyzed the expression of 9,205 human and 2,484 Plasmodium genes. We used gene expression deconvolution to estimate the relative proportion of immune cells and parasite stages in each sample and to adjust the differential gene expression analyses. Parasitemia explained much of the variation in both host and parasite gene expression and revealed that infections with higher parasitemia had more neutrophils and fewer T cells, suggesting parasitemia-dependent neutrophil recruitment and/or T cell extravasation to secondary lymphoid organs. The child’s age was also strongly correlated with gene expression variations. Plasmodium falciparum genes associated with age suggested that older children carried more male gametocytes, while host genes associated with age indicated a stronger innate response (through TLR and NLR signaling) in younger children and stronger adaptive immunity (through TCR and BCR signaling) in older children. These analyses highlight the variability in host responses and parasite regulation during P. falciparum symptomatic infections and emphasize the importance of considering the children’s age when studying and treating malaria infections. One Sentence Summary Human and P. falciparum gene expression differs according to the infection’s parasitemia and the child’s age, highlighting an age-dependent response to malaria and complex cellular and molecular -host/parasite interactions.
Human infections with the avian influenza A(H7N9) virus were first reported in China in 2013 and continue to occur. Hemagglutinin H7 administered alone is a poor immunogen necessitating evaluation of adjuvanted H7N9 vaccines.
Objective
To evaluate the immunogenicity and safety of an inactivated H7N9 vaccine with and without AS03 adjuvant, as well as mixed vaccine schedules that included sequential administration of AS03- and MF59-containing formulations and of adjuvanted and unadjuvanted formulations.
Design, Setting, and Participants
Double-blind, phase 2 trial at 5 US sites enrolled 980 adults aged 19 through 64 years from September 2013 through November 2013; safety follow-up was completed in January 2015.
Interventions
The H7N9 vaccine was given on days 0 and 21 at nominal doses of 3.75 µg, 7.5 µg, 15 µg, and 45 µg of hemagglutinin with or without AS03 or MF59 adjuvant mixed on site.
Main Outcomes and Measures
Proportions achieving a hemagglutination inhibition antibody (HIA) titer of 40 or higher at 21 days after the second vaccination; vaccine-related serious adverse events through 12 months after the first vaccination; and solicited signs and symptoms after vaccination through day 7.
Results
Two doses of vaccine were required to induce detectable antibody titers in most participants. After 2 doses of an H7N9 formulation containing 15 µg of hemagglutinin given without adjuvant, with AS03 adjuvant, or with MF59 adjuvant, the proportion achieving an HIA titer of 40 or higher was 2% (95% CI, 0%-7%) without adjuvant (n = 94), 84% (95% CI, 76%-91%) with AS03 adjuvant (n = 96), and 57% (95% CI, 47%-68%) with MF59 adjuvant (n = 92) (P < .001 for comparison of the AS03 and MF59 schedules). The 2 schedules alternating AS03-and MF59-adjuvanted formulations led to lower geometric mean titers (GMTs) of (41.5 [95% CI, 31.7-54.4]; n = 92) and (58.6 [95% CI, 44.3-77.6]; n = 96) than the group induced by 2 AS03-adjuvanted formulations (n = 96) (103.4 [95% CI, 78.7-135.9];P < .001) but higher GMTs than 2 doses of MF59-adjuvanted formulation (n = 94) (29.0 [95% CI, 22.4-37.6];P < .001).
Conclusions and Relevance
The AS03 and MF59 adjuvants augmented the immune responses to 2 doses of an inactivated H7N9 influenza vaccine, with AS03-adjuvanted formulations inducing the highest titers. This study of 2 adjuvants used in influenza vaccine formulations with adjuvant mixed on site provides immunogenicity information that may be informative to influenza pandemic preparedness programs.
Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP1) antigens play a critical role in host immune evasion. Serologic responses to these antigens have been associated with protection from clinical malaria, suggesting that antibodies to PfEMP1 antigens may contribute to natural immunity. The first N-terminal constitutive domain in a PfEMP1 is the Duffy binding-like alpha (DBL-α) domain, which contains a 300 to 400 base pair region unique to each particular protein (the DBL-α “tag”). This DBL-α tag has been used as a marker of PfEMP1 diversity and serologic responses in malaria-exposed populations. In this study, using sera from a malaria-endemic region, responses to DBL-α tags were compared to responses to the corresponding entire DBL-α domain (or “parent” domain) coupled with the succeeding cysteine-rich interdomain region (CIDR). A protein microarray populated with DBL-α tags, the parent DBL-CIDR head structures, and downstream PfEMP1 protein fragments was probed with sera from Malian children (aged 1 to 6 years) and adults from the control arms of apical membrane antigen 1 (AMA1) vaccine clinical trials before and during a malaria transmission season. Serological responses to the DBL-α tag and the DBL-CIDR head structure were measured and compared in children and adults, and throughout the season. Malian serologic responses to a PfEMP1’s DBL-α tag region did not correlate with seasonal malaria exposure, or with responses to the parent DBL-CIDR head structure in either children or adults. Parent DBL-CIDR head structures were better indicators of malaria exposure. Larger PfEMP1 domains may be better indicators of malaria exposure than short, variable PfEMP1 fragments such as DBL-α tags. PfEMP1 head structures that include conserved sequences appear particularly well suited for study as serologic predictors of malaria exposure.
Abstract Background With an estimated 249 million cases and 608,000 deaths in 2022 malaria continues to cause substantial morbidity and mortality worldwide, mostly in children in Sub-Saharan Africa due to Plasmodium falciparum. Circumsporozoite protein (CSP) coats the surface of the P. falciparum sporozoite and is the target of the two vaccines approved by the World Health Organization (WHO). CSP has three major regions: the N-terminus, the central repeat region, and the C-terminus, which contains highly variable T cell epitopes; only a fragment of the central repeat region and the C-terminus are represented by the two approved vaccines. The junction between the N-terminal Region 1 and the NANP repeat region (“junctional region”) is not represented in the approved vaccines and was recently found to be a target of protective antibody responses. Methods We used a repetitive controlled human malaria infection (rCHMI) model in which eight malaria-naïve participants were infected with P. falciparum up to three times over two years to identify immune responses associated with acquisition of natural immunity. We evaluated samples from the day of each CHMI and 18 days after each CHMI. We measured antibody responses using a peptide microarray inclusive of hundreds of P. falciparum proteins and focused our current study on the response to CSP. The amino acid sequences of CSP from the NF54 strain and 4 additional CSP variants were represented as 16-amino acid peptides with 13-amino acid overlap. Signal intensities at each amino acid position were estimated using a sliding window approach that averaged signals from adjacent overlapping peptides. Participants who comprised a “delayed parasitemia group” (n = 5) had onset of PCR-confirmed parasitemia 13 or more days after the last CHMI, a sign of developing humoral immunity. A “non-delayed parasitemia group” (n = 3) was comprised of those had onset of parasitemia within 12 or fewer days after the last CHMI. Along each amino acid position, the median signal intensities for all CSP variants are presented to describe the participants’ antibody responses at each time point. Wilcoxon signed rank test was used to compare medians between timepoints; p-values < 0.05 without adjustment for multiple comparisons were considered statistically significant. Results After three rCHMIs, participants developed antibody responses to amino acids corresponding to the junctional region and the central repeat region (P<0.05). When participants are grouped by time to parasitemia, those who showed delayed parasitemia development had strong immune responses to the junctional region while the non-delayed group did not. Antibody responses to the C-terminal region were more variable among the 5 CSP variant sequences compared to other regions. Conclusion Our results showed higher junctional region antibody response in participants with delayed time to parasitemia. We also demonstrate variable antibody response to the C-terminal region, a region with known greater genetic variability that has been previously associated with allele-specific vaccine escape and concern for decreased efficacy of current WHO-approved vaccines. Taken together, our results support future vaccine development that focuses on the conserved junctional region over the polymorphic C-terminal region.
