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Dive into the research topics where Lorraine Soisson is active.

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Featured researches published by Lorraine Soisson.


PLOS ONE | 2009

Blood Stage Malaria Vaccine Eliciting High Antigen-Specific Antibody Concentrations Confers No Protection to Young Children in Western Kenya

Bernhards Ogutu; Odika J. Apollo; Denise McKinney; Willis Okoth; Joram Siangla; Filip Dubovsky; Kathryn Tucker; John N. Waitumbi; Carter Diggs; Janet Wittes; Elissa Malkin; Amanda Leach; Lorraine Soisson; Jessica Milman; Lucas Otieno; Carolyn A. Holland; Mark E. Polhemus; Shon Remich; Christian F. Ockenhouse; Joe Cohen; W. Ripley Ballou; Samuel K. Martin; Evelina Angov; V. Ann Stewart; Jeffrey A. Lyon; D. Gray Heppner; Mark R. Withers

Objective The antigen, falciparum malaria protein 1 (FMP1), represents the 42-kDa C-terminal fragment of merozoite surface protein-1 (MSP-1) of the 3D7 clone of P. falciparum. Formulated with AS02 (a proprietary Adjuvant System), it constitutes the FMP1/AS02 candidate malaria vaccine. We evaluated this vaccines safety, immunogenicity, and efficacy in African children. Methods A randomised, double-blind, Phase IIb, comparator-controlled trial.The trial was conducted in 13 field stations of one mile radii within Kombewa Division, Nyanza Province, Western Kenya, an area of holoendemic transmission of P. falciparum. We enrolled 400 children aged 12–47 months in general good health.Children were randomised in a 1∶1 fashion to receive either FMP1/AS02 (50 µg) or Rabipur® rabies vaccine. Vaccinations were administered on a 0, 1, and 2 month schedule. The primary study endpoint was time to first clinical episode of P. falciparum malaria (temperature ≥37.5°C with asexual parasitaemia of ≥50,000 parasites/µL of blood) occurring between 14 days and six months after a third dose. Case detection was both active and passive. Safety and immunogenicity were evaluated for eight months after first immunisations; vaccine efficacy (VE) was measured over a six-month period following third vaccinations. Results 374 of 400 children received all three doses and completed six months of follow-up. FMP1/AS02 had a good safety profile and was well-tolerated but more reactogenic than the comparator. Geometric mean anti-MSP-142 antibody concentrations increased from1.3 µg/mL to 27.3 µg/mL in the FMP1/AS02 recipients, but were unchanged in controls. 97 children in the FMP1/AS02 group and 98 controls had a primary endpoint episode. Overall VE was 5.1% (95% CI: −26% to +28%; p-value = 0.7). Conclusions FMP1/AS02 is not a promising candidate for further development as a monovalent malaria vaccine. Future MSP-142 vaccine development should focus on other formulations and antigen constructs. Trial Registration Clinicaltrials.gov NCT00223990


The New England Journal of Medicine | 2011

A Field Trial to Assess a Blood-Stage Malaria Vaccine

Mahamadou A. Thera; Ogobara K. Doumbo; Drissa Coulibaly; Matthew B. Laurens; Amed Ouattara; Abdoulaye K. Kone; Ando Guindo; Karim Traore; Idrissa Traore; Bourema Kouriba; Dapa A. Diallo; Issa Diarra; Modibo Daou; Amagana Dolo; Youssouf Tolo; Mahamadou S Sissoko; Amadou Niangaly; Mady Sissoko; Shannon Takala-Harrison; Kirsten E. Lyke; Yukun Wu; William C. Blackwelder; Olivier Godeaux; Johan Vekemans; Marie-Claude Dubois; W. Ripley Ballou; Joe Cohen; Darby Thompson; Tina Dube; Lorraine Soisson

BACKGROUND Blood-stage malaria vaccines are intended to prevent clinical disease. The malaria vaccine FMP2.1/AS02(A), a recombinant protein based on apical membrane antigen 1 (AMA1) from the 3D7 strain of Plasmodium falciparum, has previously been shown to have immunogenicity and acceptable safety in Malian adults and children. METHODS In a double-blind, randomized trial, we immunized 400 Malian children with either the malaria vaccine or a control (rabies) vaccine and followed them for 6 months. The primary end point was clinical malaria, defined as fever and at least 2500 parasites per cubic millimeter of blood. A secondary end point was clinical malaria caused by parasites with the AMA1 DNA sequence found in the vaccine strain. RESULTS The cumulative incidence of the primary end point was 48.4% in the malaria-vaccine group and 54.4% in the control group; efficacy against the primary end point was 17.4% (hazard ratio for the primary end point, 0.83; 95% confidence interval [CI], 0.63 to 1.09; P=0.18). Efficacy against the first and subsequent episodes of clinical malaria, as defined on the basis of various parasite-density thresholds, was approximately 20%. Efficacy against clinical malaria caused by parasites with AMA1 corresponding to that of the vaccine strain was 64.3% (hazard ratio, 0.36; 95% CI, 0.08 to 0.86; P=0.03). Local reactions and fever after vaccination were more frequent with the malaria vaccine. CONCLUSIONS On the basis of the primary end point, the malaria vaccine did not provide significant protection against clinical malaria, but on the basis of secondary results, it may have strain-specific efficacy. If this finding is confirmed, AMA1 might be useful in a multicomponent malaria vaccine. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT00460525.).


PLOS ONE | 2009

Phase 1/2a Study of the Malaria Vaccine Candidate Apical Membrane Antigen-1 (AMA-1) Administered in Adjuvant System AS01B or AS02A

Michele Spring; James F. Cummings; Christian F. Ockenhouse; Sheetij Dutta; Randall Reidler; Evelina Angov; Elke S. Bergmann-Leitner; V. Ann Stewart; Stacey Bittner; Laure Y. Juompan; Mark G. Kortepeter; Robin Nielsen; Urszula Krzych; Ev Tierney; Lisa A. Ware; Megan Dowler; Cornelus C. Hermsen; Robert W. Sauerwein; Sake J. de Vlas; Opokua Ofori-Anyinam; David E. Lanar; Jack Williams; Kent E. Kester; Kathryn Tucker; Meng Shi; Elissa Malkin; Carole A. Long; Carter Diggs; Lorraine Soisson; Marie-Claude Dubois

Background This Phase 1/2a study evaluated the safety, immunogenicity, and efficacy of an experimental malaria vaccine comprised of the recombinant Plasmodium falciparum protein apical membrane antigen-1 (AMA-1) representing the 3D7 allele formulated with either the AS01B or AS02A Adjuvant Systems. Methodology/Principal Findings After a preliminary safety evaluation of low dose AMA-1/AS01B (10 µg/0.5 mL) in 5 adults, 30 malaria-naïve adults were randomly allocated to receive full dose (50 µg/0.5 mL) of AMA-1/AS01B (n = 15) or AMA-1/AS02A (n = 15), followed by a malaria challenge. All vaccinations were administered intramuscularly on a 0-, 1-, 2-month schedule. All volunteers experienced transient injection site erythema, swelling and pain. Two weeks post-third vaccination, anti-AMA-1 Geometric Mean Antibody Concentrations (GMCs) with 95% Confidence Intervals (CIs) were high: low dose AMA-1/AS01B 196 µg/mL (103–371 µg/mL), full dose AMA-1/AS01B 279 µg/mL (210–369 µg/mL) and full dose AMA-1/AS02A 216 µg/mL (169–276 µg/mL) with no significant difference among the 3 groups. The three vaccine formulations elicited equivalent functional antibody responses, as measured by growth inhibition assay (GIA), against homologous but not against heterologous (FVO) parasites as well as demonstrable interferon-gamma (IFN-γ) responses. To assess efficacy, volunteers were challenged with P. falciparum-infected mosquitoes, and all became parasitemic, with no significant difference in the prepatent period by either light microscopy or quantitative polymerase chain reaction (qPCR). However, a small but significant reduction of parasitemia in the AMA-1/AS02A group was seen with a statistical model employing qPCR measurements. Significance All three vaccine formulations were found to be safe and highly immunogenic. These immune responses did not translate into significant vaccine efficacy in malaria-naïve adults employing a primary sporozoite challenge model, but encouragingly, estimation of parasite growth rates from qPCR data may suggest a partial biological effect of the vaccine. Further evaluation of the immunogenicity and efficacy of the AMA-1/AS02A formulation is ongoing in a malaria-experienced pediatric population in Mali. Trial Registration www.clinicaltrials.gov NCT00385047


PLOS ONE | 2013

DNA prime/Adenovirus boost malaria vaccine encoding P. falciparum CSP and AMA1 induces sterile protection associated with cell-mediated immunity.

Ilin Chuang; Martha Sedegah; Susan Cicatelli; Michele Spring; Mark E. Polhemus; Cindy Tamminga; Noelle B. Patterson; Melanie L. Guerrero; Jason W. Bennett; Shannon McGrath; Harini Ganeshan; Maria Belmonte; Fouzia Farooq; Esteban Abot; Jo Glenna Banania; Jun Huang; Rhonda Newcomer; Lisa Rein; Dianne Litilit; Nancy O. Richie; Chloe Wood; Jittawadee Murphy; Robert W. Sauerwein; Cornelus C. Hermsen; Andrea McCoy; Edwin Kamau; James F. Cummings; Jack Komisar; Awalludin Sutamihardja; Meng Shi

Background Gene-based vaccination using prime/boost regimens protects animals and humans against malaria, inducing cell-mediated responses that in animal models target liver stage malaria parasites. We tested a DNA prime/adenovirus boost malaria vaccine in a Phase 1 clinical trial with controlled human malaria infection. Methodology/Principal Findings The vaccine regimen was three monthly doses of two DNA plasmids (DNA) followed four months later by a single boost with two non-replicating human serotype 5 adenovirus vectors (Ad). The constructs encoded genes expressing P. falciparum circumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1). The regimen was safe and well-tolerated, with mostly mild adverse events that occurred at the site of injection. Only one AE (diarrhea), possibly related to immunization, was severe (Grade 3), preventing daily activities. Four weeks after the Ad boost, 15 study subjects were challenged with P. falciparum sporozoites by mosquito bite, and four (27%) were sterilely protected. Antibody responses by ELISA rose after Ad boost but were low (CSP geometric mean titer 210, range 44–817; AMA1 geometric mean micrograms/milliliter 11.9, range 1.5–102) and were not associated with protection. Ex vivo IFN-γ ELISpot responses after Ad boost were modest (CSP geometric mean spot forming cells/million peripheral blood mononuclear cells 86, range 13–408; AMA1 348, range 88–1270) and were highest in three protected subjects. ELISpot responses to AMA1 were significantly associated with protection (p = 0.019). Flow cytometry identified predominant IFN-γ mono-secreting CD8+ T cell responses in three protected subjects. No subjects with high pre-existing anti-Ad5 neutralizing antibodies were protected but the association was not statistically significant. Significance The DNA/Ad regimen provided the highest sterile immunity achieved against malaria following immunization with a gene-based subunit vaccine (27%). Protection was associated with cell-mediated immunity to AMA1, with CSP probably contributing. Substituting a low seroprevalence vector for Ad5 and supplementing CSP/AMA1 with additional antigens may improve protection. Trial Registration ClinicalTrials.govNCT00870987.


PLOS ONE | 2008

Safety and immunogenicity of an AMA1 malaria vaccine in Malian children: results of a phase 1 randomized controlled trial.

Mahamadou A. Thera; Ogobara K. Doumbo; Drissa Coulibaly; Dapa A. Diallo; Abdoulaye K. Kone; Ando Guindo; Karim Traore; Alassane Dicko; Issaka Sagara; Mahamadou S Sissoko; Mounirou Baby; Mady Sissoko; Issa Diarra; Amadou Niangaly; Amagana Dolo; Modibo Daou; Sory I. Diawara; D. Gray Heppner; V. Ann Stewart; Evelina Angov; Elke S. Bergmann-Leitner; David E. Lanar; Sheetij Dutta; Lorraine Soisson; Carter Diggs; Amanda Leach; Alex Owusu; Marie-Claude Dubois; Joe Cohen; Jason N. Nixon

Background The objective was to evaluate the safety, reactogenicity and immunogenicity of the AMA-1-based blood-stage malaria vaccine FMP2.1/AS02A in adults exposed to seasonal malaria. Methodology/Principal Findings A phase 1 double blind randomized controlled dose escalation trial was conducted in Bandiagara, Mali, West Africa, a rural town with intense seasonal transmission of Plasmodium falciparum malaria. The malaria vaccine FMP2.1/AS02A is a recombinant protein (FMP2.1) based on apical membrane antigen-1 (AMA-1) from the 3D7 clone of P. falciparum, adjuvanted with AS02A. The comparator vaccine was a cell-culture rabies virus vaccine (RabAvert). Sixty healthy, malaria-experienced adults aged 18–55 y were recruited into 2 cohorts and randomized to receive either a half dose or full dose of the malaria vaccine (FMP2.1 25 µg/AS02A 0.25 mL or FMP2.1 50 µg/AS02A 0.5 mL) or rabies vaccine given in 3 doses at 0, 1 and 2 mo, and were followed for 1 y. Solicited symptoms were assessed for 7 d and unsolicited symptoms for 30 d after each vaccination. Serious adverse events were assessed throughout the study. Titers of anti-AMA-1 antibodies were measured by ELISA and P. falciparum growth inhibition assays were performed on sera collected at pre- and post-vaccination time points. Transient local pain and swelling were common and more frequent in both malaria vaccine dosage groups than in the comparator group. Anti-AMA-1 antibodies increased significantly in both malaria vaccine groups, peaking at nearly 5-fold and more than 6-fold higher than baseline in the half-dose and full-dose groups, respectively. Conclusion/Significance The FMP2.1/AS02A vaccine had a good safety profile, was well-tolerated, and was highly immunogenic in malaria-exposed adults. This malaria vaccine is being evaluated in Phase 1 and 2 trials in children at this site. Trial Registration ClinicalTrials.gov NCT00308061


PLOS ONE | 2009

High antibody titer against apical membrane antigen-1 is required to protect against malaria in the Aotus model.

Sheetij Dutta; JoAnn S. Sullivan; Katharine K. Grady; J. David Haynes; Jack Komisar; Adrian H. Batchelor; Lorraine Soisson; Carter Diggs; D. Gray Heppner; David E. Lanar; William E. Collins; John W. Barnwell

A Plasmodium falciparum 3D7 strain Apical Membrane Antigen-1 (AMA1) vaccine, formulated with AS02A adjuvant, slowed parasite growth in a recent Phase 1/2a trial, however sterile protection was not observed. We tested this AS02A, and a Montanide ISA720 (ISA) formulation of 3D7 AMA1 in Aotus monkeys. The 3D7 parasite does not invade Aotus erythrocytes, hence two heterologous strains, FCH/4 and FVO, were used for challenge, FCH/4 AMA1 being more homologous to 3D7 than FVO AMA1. Following three vaccinations, the monkeys were challenged with 50,000 FCH/4 or 10,000 FVO parasites. Three of the six animals in the AMA+ISA group were protected against FCH/4 challenge. One monkey did not become parasitemic, another showed only a short period of low level parasitemia that self-cured, and a third animal showed a delay before exhibiting its parasitemic phase. This is the first protection shown in primates with a recombinant P. falciparum AMA1 without formulation in Freunds complete adjuvant. No animals in the AMA+AS02A group were protected, but this group exhibited a trend towards reduced growth rate. A second group of monkeys vaccinated with AMA+ISA vaccine was not protected against FVO challenge, suggesting strain-specificity of AMA1-based protection. Protection against FCH/4 strain correlated with the quantity of induced antibodies, as the protected animals were the only ones to have in vitro parasite growth inhibitory activity of >70% at 1∶10 serum dilution; immuno-fluorescence titers >8,000; ELISA titers against full-length AMA1 >300,000 and ELISA titer against AMA1 domains1+2 >100,000. A negative correlation between log ELISA titer and day 11 cumulative parasitemia (Spearman rank r = −0.780, p value = 0.0001), further confirmed the relationship between antibody titer and protection. High titers of cross-strain inhibitory antibodies against AMA1 are therefore critical to confer solid protection, and the Aotus model can be used to down-select future AMA1 formulations, prior to advanced human trials.


PLOS ONE | 2011

Adenovirus-5-Vectored P. falciparum Vaccine Expressing CSP and AMA1. Part B: Safety, Immunogenicity and Protective Efficacy of the CSP Component

Cindy Tamminga; Martha Sedegah; David P. Regis; Ilin Chuang; Judith E. Epstein; Michele Spring; Jose Mendoza-Silveiras; Shannon McGrath; Santina Maiolatesi; Sharina Reyes; Victoria Steinbeiss; Charlotte Fedders; Kathryn Smith; Brent House; Harini Ganeshan; Jennylynn Lejano; Esteban Abot; Glenna Banania; Renato Sayo; Fouzia Farooq; Maria Belmonte; Jittawadee Murphy; Jack Komisar; Jackie Williams; Meng Shi; Donald Brambilla; Nalini Manohar; Nancy O. Richie; Chloe Wood; Keith Limbach

Background A protective malaria vaccine will likely need to elicit both cell-mediated and antibody responses. As adenovirus vaccine vectors induce both these responses in humans, a Phase 1/2a clinical trial was conducted to evaluate the efficacy of an adenovirus serotype 5-vectored malaria vaccine against sporozoite challenge. Methodology/Principal Findings NMRC-MV-Ad-PfC is an adenovirus vector encoding the Plasmodium falciparum 3D7 circumsporozoite protein (CSP). It is one component of a two-component vaccine NMRC-M3V-Ad-PfCA consisting of one adenovector encoding CSP and one encoding apical membrane antigen-1 (AMA1) that was evaluated for safety and immunogenicity in an earlier study (see companion paper, Sedegah et al). Fourteen Ad5 seropositive or negative adults received two doses of NMRC-MV-Ad-PfC sixteen weeks apart, at particle units per dose. The vaccine was safe and well tolerated. All volunteers developed positive ELISpot responses by 28 days after the first immunization (geometric mean 272 spot forming cells/million[sfc/m]) that declined during the following 16 weeks and increased after the second dose to levels that in most cases were less than the initial peak (geometric mean 119 sfc/m). CD8+ predominated over CD4+ responses, as in the first clinical trial. Antibody responses were poor and like ELISpot responses increased after the second immunization but did not exceed the initial peak. Pre-existing neutralizing antibodies (NAb) to Ad5 did not affect the immunogenicity of the first dose, but the fold increase in NAb induced by the first dose was significantly associated with poorer antibody responses after the second dose, while ELISpot responses remained unaffected. When challenged by the bite of P. falciparum-infected mosquitoes, two of 11 volunteers showed a delay in the time to patency compared to infectivity controls, but no volunteers were sterilely protected. Significance The NMRC-MV-Ad-PfC vaccine expressing CSP was safe and well tolerated given as two doses, but did not provide sterile protection. Trial Registration ClinicalTrials.gov NCT00392015


PLOS Clinical Trials | 2006

Safety and Reactogenicity of an MSP-1 Malaria Vaccine Candidate: A Randomized Phase Ib Dose-Escalation Trial in Kenyan Children

Mark R. Withers; Denise McKinney; Bernhards Ogutu; John N. Waitumbi; Jessica Milman; Odika J. Apollo; Otieno G Allen; Kathryn Tucker; Lorraine Soisson; Carter Diggs; Amanda Leach; Janet Wittes; Filip Dubovsky; V. Ann Stewart; Shon Remich; Joe Cohen; W. Ripley Ballou; Carolyn A. Holland; Jeffrey A. Lyon; Evelina Angov; José A. Stoute; Samuel K. Martin; D. Gray Heppner

Objective: Our aim was to evaluate the safety, reactogenicity, and immunogenicity of an investigational malaria vaccine. Design: This was an age-stratified phase Ib, double-blind, randomized, controlled, dose-escalation trial. Children were recruited into one of three cohorts (dosage groups) and randomized in 2:1 fashion to receive either the test product or a comparator. Setting: The study was conducted in a rural population in Kombewa Division, western Kenya. Participants: Subjects were 135 children, aged 12–47 mo. Interventions: Subjects received 10, 25, or 50 μg of falciparum malaria protein 1 (FMP1) formulated in 100, 250, and 500 μL, respectively, of AS02A, or they received a comparator (Imovax® rabies vaccine). Outcome Measures: We performed safety and reactogenicity parameters and assessment of adverse events during solicited (7 d) and unsolicited (30 d) periods after each vaccination. Serious adverse events were monitored for 6 mo after the last vaccination. Results: Both vaccines were safe and well tolerated. FMP1/AS02A recipients experienced significantly more pain and injection-site swelling with a dose-effect relationship. Systemic reactogenicity was low at all dose levels. Hemoglobin levels remained stable and similar across arms. Baseline geometric mean titers were comparable in all groups. Anti-FMP1 antibody titers increased in a dose-dependent manner in subjects receiving FMP1/AS02A; no increase in anti-FMP1 titers occurred in subjects who received the comparator. By study end, subjects who received either 25 or 50 μg of FMP1 had similar antibody levels, which remained significantly higher than that of those who received the comparator or 10 μg of FMP1. A longitudinal mixed effects model showed a statistically significant effect of dosage level on immune response (F3,1047 = 10.78, or F3, 995 = 11.22, p < 0.001); however, the comparison of 25 μg and 50 μg recipients indicated no significant difference (F1,1047 = 0.05; p = 0.82). Conclusions: The FMP1/AS02A vaccine was safe and immunogenic in malaria-exposed 12- to 47-mo-old children and the magnitude of immune response of the 25 and 50 μg doses was superior to that of the 10 μg dose.


PLOS ONE | 2011

Adenovirus 5-Vectored P. falciparum Vaccine Expressing CSP and AMA1. Part A: Safety and Immunogenicity in Seronegative Adults

Martha Sedegah; Cindy Tamminga; Shannon McGrath; Brent House; Harini Ganeshan; Jennylynn Lejano; Esteban Abot; Glenna Banania; Renato Sayo; Fouzia Farooq; Maria Belmonte; Nalini Manohar; Nancy O. Richie; Chloe Wood; Carole A. Long; David P. Regis; Francis Williams; Meng Shi; Ilin Chuang; Michele Spring; Judith E. Epstein; Jose Mendoza-Silveiras; Keith Limbach; Noelle B. Patterson; Joseph T. Bruder; Denise L. Doolan; C. Richter King; Lorraine Soisson; Carter Diggs; Daniel J. Carucci

Background Models of immunity to malaria indicate the importance of CD8+ T cell responses for targeting intrahepatic stages and antibodies for targeting sporozoite and blood stages. We designed a multistage adenovirus 5 (Ad5)-vectored Plasmodium falciparum malaria vaccine, aiming to induce both types of responses in humans, that was tested for safety and immunogenicity in a Phase 1 dose escalation trial in Ad5-seronegative volunteers. Methodology/Principal Findings The NMRC-M3V-Ad-PfCA vaccine combines two adenovectors encoding circumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1). Group 1 (n = 6) healthy volunteers received one intramuscular injection of 2×10∧10 particle units (1×10∧10 each construct) and Group 2 (n = 6) a five-fold higher dose. Transient, mild to moderate adverse events were more pronounced with the higher dose. ELISpot responses to CSP and AMA1 peaked at 1 month, were higher in the low dose (geomean CSP = 422, AMA1 = 862 spot forming cells/million) than in the high dose (CSP = 154, p = 0.049, AMA1 = 423, p = 0.045) group and were still positive at 12 months in a number of volunteers. ELISpot depletion assays identified dependence on CD4+ or on both CD4+ and CD8+ T cells, with few responses dependent only on CD8+ T cells. Intracellular cytokine staining detected stronger CD8+ than CD4+ T cell IFN-γ responses (CSP p = 0.0001, AMA1 p = 0.003), but similar frequencies of multifunctional CD4+ and CD8+ T cells secreting two or more of IFN-γ, TNF-α or IL-2. Median fluorescence intensities were 7–10 fold higher in triple than single secreting cells. Antibody responses were low but trended higher in the high dose group and did not inhibit growth of cultured P. falciparum blood stage parasites. Significance As found in other trials, adenovectored vaccines appeared safe and well-tolerated at doses up to 1×10∧11 particle units. This is the first demonstration in humans of a malaria vaccine eliciting strong CD8+ T cell IFN-γ responses. Trial Registration ClinicalTrials.gov NCT00392015


The Journal of Infectious Diseases | 2013

Molecular Basis of Allele-Specific Efficacy of a Blood-Stage Malaria Vaccine: Vaccine Development Implications

Amed Ouattara; Shannon Takala-Harrison; Mahamadou A. Thera; Drissa Coulibaly; Amadou Niangaly; Renion Saye; Youssouf Tolo; Sheetij Dutta; D. Gray Heppner; Lorraine Soisson; Carter Diggs; Johan Vekemans; Joe Cohen; William C. Blackwelder; Tina Dube; Matthew B. Laurens; Ogobara K. Doumbo; Christopher V. Plowe

The disappointing efficacy of blood-stage malaria vaccines may be explained in part by allele-specific immune responses that are directed against polymorphic epitopes on blood-stage antigens. FMP2.1/AS02(A), a blood-stage candidate vaccine based on apical membrane antigen 1 (AMA1) from the 3D7 strain of Plasmodium falciparum, had allele-specific efficacy against clinical malaria in a phase II trial in Malian children. We assessed the cross-protective efficacy of the malaria vaccine and inferred which polymorphic amino acid positions in AMA1 were the targets of protective allele-specific immune responses. FMP2.1/AS02(A) had the highest efficacy against AMA1 alleles that were identical to the 3D7 vaccine-type allele at 8 highly polymorphic amino acid positions in the cluster 1 loop (c1L) but differed from 3D7 elsewhere in the molecule. Comparison of the incidence of vaccine-type alleles before and after vaccination in the malaria vaccine and control groups and examination of the patterns of allele change at polymorphic positions in consecutive malaria episodes suggest that the highly polymorphic amino acid position 197 in c1L was the most critical determinant of allele-specific efficacy. These results indicate that a multivalent AMA1 vaccine with broad efficacy could include only a limited set of key alleles of this extremely polymorphic antigen.

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Carter Diggs

United States Agency for International Development

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D. Gray Heppner

Walter Reed Army Institute of Research

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Evelina Angov

Walter Reed Army Institute of Research

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Harini Ganeshan

Naval Medical Research Center

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Martha Sedegah

Naval Medical Research Center

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Sheetij Dutta

Walter Reed Army Institute of Research

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David E. Lanar

Walter Reed Army Institute of Research

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Fouzia Farooq

Naval Medical Research Center

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Maria Belmonte

Naval Medical Research Center

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