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Vaccines for preventing malaria (pre-erythrocytic)

  1. Patricia M Graves1,*,
  2. Hellen Gelband2

Editorial Group: Cochrane Infectious Diseases Group

Published Online: 21 JAN 2009

Assessed as up-to-date: 13 JUN 2006

DOI: 10.1002/14651858.CD006198

Database Title

Additional Information

How to Cite

Graves PM, Gelband H. Vaccines for preventing malaria (pre-erythrocytic). Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD006198. DOI: 10.1002/14651858.CD006198.

Author Information

  1. 1

    EpiVec Consulting, Atlanta, Georgia, USA

  2. 2

    Resources for the Future, Washington, DC, USA

*Patricia M Graves, EpiVec Consulting, Atlanta, Georgia, GA 30341, USA. epivec@comcast.net. pmgraves@aol.com.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 21 JAN 2009

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Characteristics of included studies [ordered by study ID]
Alonso 2005a
MethodsRandomized controlled trial

Generation of allocation sequence: computer generated in blocks of 6

Allocation concealment: central randomization was done at GlaxoSmithKline and the code released to the investigators after completion of follow up; opaque masked and coded syringes were used

Blinding: investigator, participants, and outcome assessors blinded for first 6 months; investigators were not blinded during next 12 months

Inclusion of all randomized participants: 1493/1605 (93.0%) of those randomized received 3 doses; 1380/1605 (86.0%) completed 6-month follow up (92.4% of those who received 3 doses); 1442 entered single-blind phase of whom 1319 (91.5%) completed follow up

Length of follow up: 18 months after third dose
ParticipantsNumber: 1605 children

Inclusion criteria: aged 1 to 4 years; resident in study area; full immunization with Expanded Programme of Immunization (EPI) vaccines; parental consent

Exclusion criteria: history of allergic disease; packed cell volume ≤ 25%; weight for height ≤ 3 Z score; clinically significant chronic or acute disease; abnormal haematology or biochemistry variables
Interventions1. RTS,S vaccine: 3 doses, 25 µg in 250 µL AS02A adjuvant, intramuscularly in deltoid (alternating arms) at 0, 1, and 2 months
2. Pneumococcal conjugate vaccine (under 24-months old; first and third doses) plus Hib vaccine (second dose) or hepatitis B vaccine (over 24-months old; 3 doses)
Outcomes1. Time to first clinical episode of symptomatic Plasmodium falciparum malaria (case definition: child presenting with temperature > 37.5 °C and parasitaemia > 2500/µL)
2. Clinical episodes of malaria
3. Malaria needing admission: (P. falciparum sole cause of illness or important contributing factor)
4. All-cause admission
5. Severe malaria (derived from World Health Organization definition: asexual P. falciparum parasitaemia; no other more probable cause of illness; plus composite of severe malaria anaemia (packed cell volume < 15%), cerebral malaria (Blantyre coma score < 2), and severe disease of other body systems (multiple seizures, prostration, hypoglycaemia, clinically suspected acidosis, or circulatory collapse)
6. Prevalence of parasitaemia
7. Prevalence of anaemia (packed cell volume < 25%)
8. Geometric mean parasite density in first clinical episode
9. Geometric mean parasite density in parasitaemic children at 6.5 months
10. Geometric mean titre to CS protein and hepatitis B surface antigen (HBsAg)
11. Seropositivity rates for anti-CS antibody (> 0.5 international units/mL) and anti-hepatitis B surface antigen (HBsAg) antibody (≥ 10 international units/mL)
12. Adverse events
NotesLocation: within 10 km radius of Manhica, Mozambique where the entomological inoculation rate in 2002 was 38 infective bites/year

Method of surveillance: passive surveillance of illness and adverse events through health centre staffed 24/7; observation for 1 h after vaccination and once/day at home for 3 days after each dose for adverse events; home visits once per month starting 60 days after third dose to check residence and document unreported adverse events; complete blood count done 1 month after dose 3; creatinine, alanine aminotransferase (ALT), and bilirubin at months 1 and 6.5 after dose 3; cross-sectional surveys with blood slide and axillary temperature taken at 6.5 months and 18 months after dose 3

This trial reported in same publication as Alonso 2005b




Alonso 2005ab
MethodsStudy reference created for the reporting of adverse event data, which were reported jointly in the two trial reports (see Alonso 2005a and Alonso 2005b)
ParticipantsNot applicable
InterventionsNot applicable
OutcomesNot applicable
NotesNot applicable




Alonso 2005b
MethodsRandomized controlled trial

Generation of allocation sequence: computer generated in blocks of 6

Allocation concealment: central randomization was done at GlaxoSmithKline and the code released to the investigators after completion of follow up; opaque and masked coded syringes were used

Blinding: investigator, participants, and outcome assessors blinded for first 6 months; investigators were not blinded during next 12 months

Inclusion of all randomized participants: 383/417 (91.8%) of those randomized received 3 doses; 299/417 (71.7%) completed 6 months follow up (78.1% of those who received 3 doses); 352 entered single-blind phase of whom 320 (90.9%) completed follow up

Length of follow up: 18 months after third dose
ParticipantsNumber: 417 children

Inclusion criteria: age 1 to 4 years; resident in study area; full Expanded Programme of Immunization (EPI) immunization; parent's consent

Exclusion criteria: history of allergic disease; packed cell volume ≤ 25%; weight for height ≤ 3 Z score; clinically significant chronic or acute disease; abnormal haematology or biochemistry variables
Interventions1. RTS,S vaccine: 3 doses, 25 µg in 250 µL AS02A adjuvant, intramuscularly in deltoid (alternating arms) at 0, 1, and 2 months
2. 7-valent pneumococcal conjugate vaccine (< 24-months old; doses 1 and 3) plus Hib vaccine (dose 2) or hepatitis B vaccine (> 24-months old; 3 doses)

4 weeks before start of surveillance, presumptive treatment with amodiaquine and sulfadoxine-pyrimethamine was given; those children positive 2 weeks later were treated with second-line drug and excluded from follow up
Outcomes1. Time to first infection with Plasmodium falciparum malaria (case definition: presenting with temperature > 37.5 °C and parasitaemia > 2500/µL)
2. Clinical episodes of malaria
3. Malaria needing admission (P. falciparum sole cause of illness or important contributing factor)
4. All-cause admission
5. Severe malaria (derived from World Health Organization definition: asexual P. falciparum parasitaemia; no other more probable cause of illness; plus composite of severe malaria anaemia (packed cell volume < 5%), cerebral malaria (Blantyre coma score < 2), and severe disease of other body systems (multiple seizures, prostration, hypoglycaemia, clinically suspected acidosis, or circulatory collapse)
6. Prevalence of parasitaemia
7. Prevalence of anaemia (packed cell volume < 25%)
8. Geometric mean parasite density in first clinical episode
9. Geometric mean parasite density in parasitaemic children at 6.5 months
10. Geometric mean titre to CS protein and hepatitis B surface antigen (HBsAg)
11. Seropositivity for anti-CS antibody (> 0.5 international units/mL) and anti-hepatitis B surface antigen (HBsAg) antibody (≥ 10 international units/mL)
12. Adverse events
NotesLocation: Ilha Josina, a lowland area 55 km north of Manhica, Mozambique with pronounced seasonality of transmission and more intense transmission than in Manhica

Method of surveillance: active surveillance for infection by morbidity questionnaire, axillary temperature, and blood slides at home visits starting 2 weeks after dose 3, every 2 weeks for 2.5 months then monthly for 2 months; observation for 1 h after vaccination and once/day at home for 3 days after each dose for adverse events; complete blood count done 1 month after dose 3; creatinine, alanine aminotransferase (ALT), and bilirubin at months 1 and 6.5 after dose 3; cross-sectional surveys with blood slide and axillary temperature taken at 6.5 months and 18 months after dose 3

This trial reported in same publication as Alonso 2005a




Bojang 2001
MethodsRandomized controlled trial

Generation of allocation sequence: externally generated list; in village blocks

Allocation concealment: each individual's vaccine doses were packaged in sealed boxes labelled with a unique randomization number; vaccines given by nurses with no other role in study

Blinding: double blind

Inclusion of all randomized participants: 264/306 (86.3%) received 3 doses; 250/306 (81.7%) completed follow up to year 1 (94.7% of those who received 3 doses); 158 received dose 4 and were followed up in second year

Length of follow up: 15 weeks in 1998; and 9 weeks in 1999 transmission season
ParticipantsNumber: 306 males

Inclusion criteria: age 18 to 45 years; no clinically significant disease.

Exclusion criteria: known allergy to any vaccine or sulfadoxine-pyrimethamine; chronic clinically significant pulmonary, cardiovascular, hepatic, or renal functional abnormality; history of splenectomy; packed cell volume < 30%; any blood transfusions within last month; any immunosuppressive drugs, previous vaccine with MPL- or QS-21-containing vaccine; participation in another trial; any other vaccine or immunoglobulin within last 2 weeks; known human immunodeficiency virus (HIV) infection
Interventions1. RTS,S vaccine: 3 doses (50 µg per 0.5 mL dose) on days 0, 28, and 150; dose 4 given in following year (1999)
2. Rabies human diploid cell vaccine

Sulfadoxine-pyrimethamine (3 tablets) was given to all participants 2 weeks before dose 3
Outcomes1. Time to first asexual Plasmodium falciparum infection
2. Symptomatic malaria (case definition: presence of P. falciparum at any density with at least one of the following: fever (axillary temp ≥ 37.5 °C; history of fever in last 24 h); malaise; chills; headache; myalgia; arthralgia; and nausea, with no other obvious cause)
3. Malaria infection
4. Packed cell volume
5. Anti-circumsporozoite protein antibodies
6. T-cell responses to RTS,S and hepatitis B surface antigen
7. Adverse events
NotesLocation: 6 villages in Upper River Division, The Gambia, where malaria occurs during the rainy season (July to November) with greatest incidence in October to November

Entomological inoculation rate: 1 to 50 infective bites per person per year

Method of surveillance: daily home visits for symptom surveillance and weekly blood slide; passive surveillance




Bojang 2005a
MethodsRandomized controlled trial

Generation of allocation sequence: random selection from list of eligible participants sent to external statistician at GlaxoSmithKline Biologicals, in ratio of 2 vaccine to 1 placebo per dose level

Allocation concealment: masked identical syringes prepared by staff otherwise uninvolved in trial

Blinding: investigators, participants, and evaluators blinded
Inclusion of all randomized participants: 85/90 (94%) completed follow up

Length of follow up: 30 days after last dose
ParticipantsNumber: 90 children

Inclusion criteria: age 6 to 11 years; no clinically significant chronic or acute disease (chronic hepatitis B carriers were not excluded)

Exclusion criteria: known allergy to any vaccine; severe malnutrition (weight for height < 3 Z scores); haematocrit < 30%
Interventions1. RTS,S/AS02A vaccine: 10 µg in 0.1 mL adjuvant; 3 doses at 0, 1, and 3 month intervals
2. RTS,S/AS02A vaccine: 25 µg in 0.25 mL adjuvant; 3 doses at 0, 1, and 3 month intervals
3. RTS,S/AS02A vaccine: 50 µg in 0.5 mL adjuvant; 3 doses at 0, 1, and 3 month intervals
4. Rabies human diploid cell vaccine (Merieux HDCV): single-dose vial with diluent; 3 doses 0, 1, and 3 month intervals plus dose 4 given after trial completion (RTS,S groups were also offered 3 doses of rabies vaccine after trial completion)

Increasing doses of vaccine were given in a dose-escalating fashion, ie dose groups were staggered at 10 day intervals
Outcomes1. Injection site pain
2. Swelling > 50 mm and persisting > 24 h
3. Limitation of arm motion
4. Fever
5. Headache
6. Malaise
7. Nausea
8. Haemoglobin, haematocrit, white blood cell count, and platelets on days 14, 60, and 104
9. Creatinine and alanine aminotransferase (ALT) on days 14, 60, and 104
10. Antibody to circumsporozoite protein repeat epitopes
11. Circulating hepatitis B surface antigen
12. Anti-hepatitis B surface antigen (HbSAg) antibodies
NotesLocation: village of Dampha Kunda, near Basse, Upper River Division, The Gambia; highly seasonal malaria with peak in October to November

Method of surveillance: home visits daily for 3 days or until symptoms resolved; case reporting on standardized forms by study nurse in village or at clinic in Basse

This trial reported in same publication as Bojang 2005a




Bojang 2005b
MethodsRandomized controlled trial

Generation of allocation sequence: random selection from list of eligible participants sent to external statistician at GlaxoSmithKline Biologicals, in ratio 2 vaccine to 1 placebo per dose level

Allocation concealment: masked identical syringes prepared by staff otherwise uninvolved in trial

Blinding: investigators, participants, and evaluators blinded
Inclusion of all randomized participants: 130/135 (96.3%) completed follow up

Length of follow up: 30 days after last dose
ParticipantsNumber: 135 children

Inclusion criteria: age 1 to 5 years; no clinically significant chronic or acute disease (chronic hepatitis B carriers were not excluded)

Exclusion criteria: known allergy to any vaccine; severe malnutrition (weight for height < 3 Z scores); haematocrit < 30%
Interventions1. RTS,S/AS02A vaccine: 10 µg in 0.1 mL adjuvant; 3 doses at 0, 1, and 3 month intervals
2. RTS,S/AS02A vaccine: 25 µg in 0.25 mL adjuvant; 3 doses at 0, 1, and 3 month intervals
3. RTS,S/AS02A vaccine: 50 µg in 0.5 mL adjuvant; 3 doses at 0, 1, and 3 month intervals
4. Rabies human diploid cell vaccine (Merieux HDCV): single-dose vial with diluent; 3 doses at 0, 1, and 3 month intervals plus dose 4 given after trial completion; (vaccine groups were also offered 3 doses of rabies vaccine after trial completion)

Increasing doses of vaccine were given in a dose-escalating fashion, ie dose groups were staggered at 10 day intervals
Outcomes1. Injection site pain
2. Swelling > 20 mm
3. Fever
4. Drowsiness
5. Loss of appetite
6. Irritability/fussiness
7. Haemoglobin, haematocrit, white blood cell count, and platelets on days 14, 60, and 104
8. Creatinine and alanine aminotransferase (ALT) on days 14, 60, and 104
9. Antibody to circumsporozoite protein repeat epitopes
10. Circulating hepatitis B surface antigen (HBsAG) antigen
11. Anti-HbSAg antibodies
NotesLocation: village of Dampha Kunda, near Basse, Upper River Division, The Gambia; highly seasonal malaria with peak in October to November

Method of surveillance: home visits daily for 3 days or until symptoms resolved; case reporting on standardized forms by study nurse in village or at clinic in Basse

This trial reported in same publication as Bojang 2005b




Brown 1994
MethodsRandomized controlled trial

Generation of allocation sequence: not stated

Allocation concealment: coded vials of similar appearance for vaccine and control; prepared externally by the Swiss Serum and Vaccine Institute and provided to the investigators

Blinding: double blind

Inclusion of all randomized participants: 84% completed the study

Length of follow up: 4 months after last dose
ParticipantsNumber: 199 male Thai soldiers; malaria-naive (44) or malaria-experienced (155)

Inclusion criteria: age 18 to 45 years

Exclusion criteria: significant cardiac, hepatic, renal, or immunological disease; recent surgery; human immunodeficiency virus (HIV) antibody positivity; use of immunosuppressive drugs; anaemia (haemoglobin < 10 g/dL); diabetes; history of significant allergy
Interventions1. R32Tox-A vaccine: 3 doses (320 µg per 0.4 mL dose, adsorbed onto aluminium hydroxide) at 8 and 16 weeks
2. Tetanus/diphtheria toxoids: 10 and 1 Lf units, respectively, in first dose and phosphate buffered saline in subsequent doses
Outcomes1. Malaria cases (case definition: positive slide)
2. Time to malaria diagnosis
3. Polymerase chain reaction (PCR)-detected CS sequences from cases
4. Anti-R32LR IgG and IgM levels
5. Anti-toxin A antibody
6. Adverse events
NotesLocation: Ubon Ratchatani Province on Thai-Cambodian border

Participants were vaccinated in a non-endemic area and then deployed in camps in endemic areas

Method of surveillance: bi-weekly active and passive case detection




Genton 2005
MethodsRandomized controlled trial

Generation of allocation sequence: by computer, in blocks of 8 (5 vaccine and 3 placebo), by independent statistician

Allocation concealment: syringes prepared and labelled with randomization number by independent pharmacist

Blinding: investigators, participants, and outcome assessors blinded

Inclusion of all randomized participants: 14/16 (87.5%) completed follow up

Length of follow up: 21 days after challenge
ParticipantsNumber: 16 adults

Inclusion criteria: age 18 to 45 years; either gender; live near Lausanne, Switzerland; scored ≥ 10/12 correct on test of understanding

Exclusion criteria: history of malaria; possible exposure to malaria within the previous 6 months; positive serology for Plasmodium falciparum in indirect fluorescent antibody test; history of severe reactions or allergy to mosquito bites, artemether-lumefantrine (Riamet), or vaccines; pregnancy or lactation; confirmed or suspected immunodeficient condition; chronic or active neurological, gastrointestinal, cardiovascular, or respiratory disease; haemoglobinopathies; history of > 2 hospitalizations for invasive bacterial infections; requirement of any chronic medication; suspected or known current alcohol or illegal drug abuse (excluding cannabis); any other significant finding which, in the opinion of the investigator, would significantly increase the risk of having an adverse outcome from participating in this protocol or of dropping out of the study; body mass index < 18 kg/m2 or > 32 kg/m2; evidence of past or present psychiatric condition; seropositivity for human immunodeficiency virus (HIV), hepatitis C or B (other than antibody to hepatitis B surface antigen (HBsAg)); 10-year risk of coronary heart disease > 10%; clinically significant deviation from normal range in biochemistry or haematology blood tests or in urinalysis
Interventions1. Pf CS102: 2 doses (30 µg each dose) in Montanide ISA 720 adjuvant as 0.5 mL intramuscular injection on days 0 and 60
2. Adjuvant only, on same schedule
Outcomes1. Time between experimental challenge and detection of blood-stage parasites in thick blood film
2. Time between experimental challenge and polymerase chain reaction (PCR) detection of blood stage parasites
3. Adverse events
4. Humoral and cell-mediated immune responses before and after sporozoite challenge
NotesLocation: Lausanne, Switzerland

Challenge by bite of 5 sporozoite-infected mosquitoes in Nijmegen, the Netherlands, 2 weeks after dose 2

Methods of surveillance: for adverse events, used diary card for self report of symptoms up to day 4, and solicited and unsolicited events assessed on days 4 and 14 after each dose; for efficacy, participants were seen once per day from day 3 to 5 after challenge, twice per day from day 6 to 15, and once per day from day 15 to 21




Guiguemde 1990
MethodsRandomized controlled trial

Generation of allocation sequence: stated to be randomized, but method not clear

Allocation concealment: unclear

Blinding: double blind

Inclusion of all randomized participants: 109/123 (88.6%) infants completed the study

Length of follow up: 5 months
ParticipantsNumber: 123 infants

Inclusion criteria: age 3 to 5 months; weight > 3 kg; good general health; parents' consent

Exclusion criteria: fever ≥ 38 °C; positive blood slide for Plasmodium falciparum
Interventions1. (NANP)3-tetanus toxoid vaccine: 3 doses (subcutaneous, 100 µg)
2. Tetanus toxoid (TT) and NANP)3-TT vaccine: 2 doses TT and 1 dose vaccine
3. Tetanus toxoid (TT): 3 doses, 1 month apart (Expanded Programme of Immunization (EPI) schedule)
Outcomes1. Infection with malaria
2. Cases of malaria (case definition: rectal temperature ≥ 38 °C with P. falciparum density ≥ 10,000/µL and no other aetiology for the fever)
3. Anaemia (packed cell volume)
4. Proportion with seroconversion to NANP at day 75
5. Proportion with "efficacious seroconversion" (4-fold elevation in titre) at day 75
6. Absence of parasites at end of immunization
7. Adverse events
NotesLocation: Vallee du Ko, north of Bobo-Dioulasso, Burkina Faso; area of permanent malaria transmission with maxima in July and November




Kester 2001
MethodsRandomized controlled trial

Generation of allocation sequence: random (method not stated) for included trial subgroups, balanced for sex and antibodies to hepatitis B surface antigen (HBsAg)

Allocation concealment: not used

Blinding: included subgroups were double blind

Inclusion of all randomized participants: 46 participants were immunized; 24 of these were subsequently challenged

Length of follow up: 60 days after last dose
ParticipantsNumber: 46 malaria-naive adults

Inclusion criteria: age 18 to 45 years; written informed consent

Exclusion criteria: splenectomy; any cardiovascular, hepatic, or renal abnormalities; allergy to any antimalarial drugs; immunodeficiency; pregnancy; conditions that would increase risk of adverse outcome from malaria
Interventions1. RTS,S/SBAS2 vaccine: 3 doses in groups; C = 50 µg vaccine; D = 25 µg vaccine; E = 10 µg vaccine
2. Engerix hepatitis B vaccine (group F)

Doses at 0, 1, and 9 months
Outcomes1. Incidence of malaria
2. Time to malaria infection
3. Adverse events
NotesLocation: USA

Artificial challenge with sporozoite infected mosquitoes, 2 to 4 weeks after last vaccine dose




Moorthy 2004b
MethodsRandomized controlled trial

Generation of allocation sequence: generated by Data Safety and Monitoring Board (assume by computer); block randomization to avoid imbalances within villages and overall

Allocation concealment: opaque sealed envelopes
Blinding: investigators, participants, and assessors blinded (including separate assessors for reactogenicity and outcomes)

Inclusion of all randomized participants: 320/372 (86.0%) received 3 doses, 296/372 (79.6%) completed follow up (92.5% of those receiving 3 doses)
Length of follow up: 11 weeks after dose 3
ParticipantsNumber: 372 males

Inclusion criteria: age 15 to 45 years; living in study villages

Exclusion criteria: any chronic illness detected by clinical evaluation; alanine aminotransferase (ALT) > 42 international units/L; creatinine > 130 µmol/L; packed cell volume < 30%; positive antibody ELISA to human immunodeficiency virus (HIV) 1 or HIV2; simultaneous participation in another clinical trial; blood transfusion in month prior to vaccination; previous experimental malaria vaccination; administration of another vaccine within 2 weeks of vaccination; previous rabies vaccination; allergy to any previous vaccine or to sulfadoxine-pyrimethamine; history of splenectomy; any treatment with immunosuppressive drugs
Interventions1. DNA ME-TRAP vaccine: 2 mg on days 0 and 21 (2 intramuscular injections each time, 1 into each deltoid muscle) and MVA ME-TRAP 1.5 x 10^8 plaque forming units on day 42 (4 intradermal injections, 2 in each deltoid)
2. Rabies vaccine (Chiron Behring): 3 doses on same schedule and routes of administration

Sulfadoxine-pyrimethamine given 2 weeks before dose 3 (4 weeks before beginning of surveillance)
Outcomes1. Time to first infection with Plasmodium falciparum
2. Clinical malaria (case definition: asexual P. falciparum at any level plus temperature ≥ 37.5 °C plus any of headache, myalgia, arthralgia, malaise, nausea, dizziness, or abdominal pain)
3. P. falciparum parasitaemia
4. Packed cell volume
5. Adverse events
NotesLocation: North Bank Division, The Gambia; 13 villages near alluvial flood plain

Malaria incidence in adult men was 72% over 11 weeks of high transmission season in a low-transmission year

Entomological inoculation rate: estimated at 10 to 20 per year
Method of surveillance: twice weekly home visits and minimum weekly blood slides; passive case detection by study nurses residing in study villages; observation for adverse events for 1 h after vaccination and at home visits on days 1, 2, and 7




Sherwood 1996
MethodsRandomized controlled trial

Generation of allocation sequence: participants were in self-selected pairs, assignment in each pair was random (method not stated)

Allocation concealment: unclear

Blinding: double blind

Inclusion of all randomized participants: 69/76 (90.8%) completed the study

Length of follow up: 6 months after last vaccination
ParticipantsNumber: 76 males in 38 pairs sleeping adjacently in houses in 5 villages

Inclusion criteria: age 18 to 30 years; willing to reside in study area for 12 months and use no antimalarial prophylaxis or bed net during study; human immunodeficiency virus (HIV) negative

Exclusion criteria: evidence of cardiac, pulmonary, renal, or immunologic disease; antibody to HIV
Interventions1. Recombinant R32LRToxA vaccine ((NANP)15-(NVDP)2-LR covalently linked to Pseudomonas aeruginosa toxin A): 3 doses at 1, 8, and 24 weeks; each dose was 175 µg peptide and 225 µg toxin A
2. Recombinant hepatitis B vaccine (Engerix B)

In both groups: parasitaemia cleared with quinine sulfate (650 mg 3 times per day for 3 days) and doxycycline (100 mg 2 times per day for 7 days) before each vaccination, and after last vaccination quinine sulfate (as above) and doxycycline (100 mg 2 times per day for 28 days) to eliminate liver stages
Outcomes1. Number of symptomatic Plasmodium falciparum cases after 1, 2, or 3 doses (case definition: positive blood slide together with fever, chills, sweats, headache, cough, or diarrhoea)
2. Number of fever cases
3. Number of days until P. falciparum positive blood slide
4. Density of P. falciparum
5. Prevalence of P. falciparum, P. vivax, and P. malariae
6. Levels of anti-R32LR antibody by ELISA
7. Levels of antisporozoite antibody by indirect fluorescent antibody
8. Lymphocyte proliferation to R32 LR
9. Adverse events
NotesLocation: near Saradidi, Western Kenya; malaria incidence 90% over 4 months

Method of surveillance: scheduled blood slides taken weekly; slides made at daily home visits if symptoms reported


 
Characteristics of excluded studies [ordered by study ID]
StudyReason for exclusion
Bejon 2005Nonrandomized review and methodology study
Doherty 1999Nonrandomized study
Edelman 2002Nonrandomized study
Epstein 2004Nonrandomized study
Fries 1992Nonrandomized study
Gordon 1990Nonrandomized study
Gordon 1995Nonrandomized study
Heppner 1996Nonrandomized study
Hoffman 19942 groups with very small numbers of participants, and only 1 group randomized
Hoffman 2002Nonrandomized study
Le 1999Nonrandomized open label dose-finding safety and immunogenicity study
McConkey 2003Nonrandomized immunogenicity study
Moorthy 2003Nonrandomized safety and immunogenicity study; no placebo group
Moorthy 2004cQuasi-randomized safety and immunogenicity study; no placebo group
Nardin 2000Nonrandomized immunogenicity study
Nardin 2001Nonrandomized immunogenicity study
Roggero 1999Nonrandomized study
Stoute 1998Participants were randomized between different doses of the vaccine, but not randomized between vaccine and control groups
Walther 2005Nonrandomized study


 
Comparison 1. CS-NANP vaccine versus control
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 New malaria infection3307Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.82, 1.35]
 
Comparison 2. CS-102 vaccine versus control
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Nausea1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
 2 Fever1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
 3 Malaise1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
 
Comparison 3. RTS,S vaccine versus control
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 New infection: by type of challenge3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
    1.1 Experimental challenge
124Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.35, 0.90]
    1.2 Natural challenge
2723Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.87, 1.06]
 2 New infection: by age group3747Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.86, 1.04]
    2.1 Adults
2330Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.79, 1.17]
    2.2 Children
1417Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.85, 1.04]
 3 Clinical malaria episodes21911Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.66, 0.88]
    3.1 Adults
1306Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.63, 1.23]
    3.2 Children
11605Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.63, 0.87]
 4 Clinical malaria episodes: by year1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
    4.1 Year 1 (adults)
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.2 Year 2 after booster (adults)
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 5 Severe malaria1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
 6 Malaria requiring admission1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
 7 Admission to hospital for any cause1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
 8 Prevalence of parasitaemia2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
    8.1 After 6 months
22022Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.62, 0.89]
    8.2 After 18 months
21794Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.65, 0.99]
 9 Anaemia (packed cell volume < 25%)2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
    9.1 After 6 months
22022Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.42, 1.12]
    9.2 After 18 months
11442Risk Ratio (M-H, Fixed, 95% CI)0.20 [0.01, 4.14]
 10 Adverse events5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
    10.1 Injection site pain
57502Risk Ratio (M-H, Fixed, 95% CI)1.37 [1.28, 1.45]
    10.2 Arm pain
1138Risk Ratio (M-H, Fixed, 95% CI)1.76 [0.80, 3.89]
    10.3 Swelling
47329Risk Ratio (M-H, Fixed, 95% CI)9.85 [6.61, 14.67]
    10.4 Induration
1138Risk Ratio (M-H, Fixed, 95% CI)8.26 [0.50, 136.74]
    10.5 Warmth
1138Risk Ratio (M-H, Fixed, 95% CI)4.94 [0.67, 36.25]
    10.6 Tenderness
1138Risk Ratio (M-H, Fixed, 95% CI)1.82 [0.83, 4.01]
    10.7 Erythema
1138Risk Ratio (M-H, Fixed, 95% CI)2.82 [0.68, 11.68]
    10.8 Arm motion limitation
31272Risk Ratio (M-H, Fixed, 95% CI)4.32 [2.95, 6.33]
    10.9 Myalgia
21003Risk Ratio (M-H, Fixed, 95% CI)1.16 [0.74, 1.80]
    10.10 Arthralgia
21003Risk Ratio (M-H, Fixed, 95% CI)1.26 [0.87, 1.83]
    10.11 Axillary adenopathy
1138Risk Ratio (M-H, Fixed, 95% CI)2.12 [0.26, 17.00]
    10.12 Headache
31272Risk Ratio (M-H, Fixed, 95% CI)1.47 [1.21, 1.78]
    10.13 Fever
31527Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.68, 1.46]
    10.14 Feverishness (subjective)
1138Risk Ratio (M-H, Fixed, 95% CI)8.26 [0.50, 136.74]
    10.15 Chills
1138Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.30, 3.70]
    10.16 Drowsiness
1392Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.53, 2.58]
    10.17 Loss of appetite
1392Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.57, 1.88]
    10.18 Nausea
21134Risk Ratio (M-H, Fixed, 95% CI)1.58 [0.99, 2.51]
    10.19 Malaise
31360Risk Ratio (M-H, Fixed, 95% CI)1.67 [1.30, 2.14]
    10.20 Irritability/fussiness
1392Risk Ratio (M-H, Fixed, 95% CI)1.57 [0.83, 2.98]
    10.21 General (fever, irritability, drowsiness, anorexia)
15838Risk Ratio (M-H, Fixed, 95% CI)2.38 [1.47, 3.86]
    10.22 Any event preventing normal activity
11876Risk Ratio (M-H, Fixed, 95% CI)1.09 [1.02, 1.16]
 11 Severe adverse events13815Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.62, 0.85]
    11.1 Up to 6 months
11876Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.61, 0.85]
    11.2 6 to 18 months
11939Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.53, 1.07]
 
Comparison 4. ME-TRAP vaccine versus control
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 New malaria infection1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
 2 Clinical malaria episodes1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
 3 Density of Plasmodium falciparum1Mean Difference (IV, Fixed, 95% CI)Totals not selected
 4 Mean packed cell volume1Mean Difference (IV, Fixed, 95% CI)Totals not selected
 5 Adverse events1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
    5.1 Limited arm motion
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    5.2 Pain at injection site
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    5.3 Local discolouration
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    5.4 Induration
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    5.5 Blister at injection site
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    5.6 Headache
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    5.7 Objective fever
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    5.8 Malaise
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    5.9 Nausea
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
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