A systematic review on malaria and dengue vaccines for the effective management of these mosquito borne diseases: Improving public health

Figures & data

Figure 1. Prisma flow diagram.

Table 1. Key attributes of published research on dengue vaccination.

Author and Year	Country	Study Design	Study Duration	Vector-Borne Disease	Study Population	Sample Size			Vaccine	Follow-up	Findings
						Vaccinated		Control/ Placebo
Rivera et al.^Citation26	8 countries	RCT	September 2016 – March 2017	Dengue	Pediatrics	13 380		6687	TAK-003	4–4.5x years	TAK-003 was efficacious against symptomatic dengue over 3 years.
Kallas et al.^Citation27	Brazil	RCT	Nov 5, 2013, – Sept 21, 2015	Dengue	Adults	DENV-naive	114	41	Butantan-DV and TV003	5 years	Butantan-DV and TV003 were safe and induced robust, balanced neutralizing antibody responses against the four DENV serotypes.
						DENV-exposed	116	29
Sridhar et al.^Citation28	3 countries	Case-Cohort Study	N/A	Dengue	Pediatrics	2384		1194	CYD-TDV administered subcutaneously.	6 years	CYD-TDV protected against severe VCD and hospitalization for VCD for 5 years’ in persons who had exposure to dengue before vaccination
Vannice et al.^Citation29	Multiple countries of Asia and Latin America	Prospective Cohort and Case control studies	N/A	Dengue	Pediatrics	20,762		10,382	Dengvaxia	4 years	Manufacturers’ risk management plans (RMPs) and post-licensure monitoring with strong surveillance.
Barranco-Santana et al.^Citation30	4 countries	RCT	16 November 2011–2 August 2013	Dengue	Adults & Pediatrics	498		222	CYD-TDV administered subcutaneously.	3 years	TDV is generally well tolerated in people aged 1.5–45 years who live in dengue-endemic countries.
B. Guy et al.^Citation31	5 countries	RCT	NA	Dengue	Pediatrics	2669		1333	CYD-TDV administered subcutaneously.	25 months	CYD-TDV is efficacious with a satisfactory safety profile meeting the WHO standards in maintaining the dengue mortality rates by 50%.
Villar, Dayan et al.^Citation32	5 countries	RCT	June 2011 – March 2012	Dengue	Pediatrics	13,920		6949	CYD-TDV administered subcutaneously.	25 months	The CYD-TDV dengue vaccine was efficacious against VCD and severe VCD and led to fewer hospitalizations for VCD
Capeging et al.^Citation33	5 countries	RCT	June 3, 2011–Dec 01, 2011	Dengue	Pediatrics	6710		3350	CYD-TDV administered subcutaneously.	25 month	Our findings show that CYD-TDV was safe and efficacious when given as a three-dose schedule to 2–14 year-olds.
Dayan et al.^Citation34	Brazil	RCT	Aug 19 – Oct 20, 2010	Dengue	Children & Adolescent	89		46	CYD-TDV administered subcutaneously.	13 months	CYD-TDV vaccination elicited a neutralizing antibody response against all four dengue virus serotypes and was well-tolerated in children and adolescents
Durbin et al.^Citation35	USA	RCT	July 2010 – Feb 2011	Dengue	Adults	80		32	TV001, TV002, TV003, TV004 administered subcutaneously.	6 months	TV003 induced greater antibody response in 90% of flavivirus-naive vaccines.
Villar et al.^Citation36	Latin America	RCT	October 2009 – February 2010	Dengue	Pediatrics	401		199	CYD-TDV administered subcutaneously.	28 days	CYD-TDV had a favorable safety profile and antibody responses against all 4 dengue virus serotypes.
Hss, Koh et al.^Citation37	Malaysia	RCT	December 2010 – August 2012	Dengue	Pediatrics	199		55	CYD-TDV administered subcutaneously.	6 months	Satisfactory safety profile and a balanced humoral immune response against all four DENV serotypes for CYD-TDV
Lanata et al.^Citation38	USA	RCT	September 2008 – February 2009	Dengue	Pediatrics	199		99	CYD-TDV administered subcutaneously.	12 months	A 3-dose regimen of CYD-TDV had a good safety profile and elicited a robust antibody response.
Sabchareon et al.^Citation39	Thailand	RCT	Feb 5, 2009 – Feb 5, 2010	Dengue	Pediatrics	2666		1331	CYD-TDV administered subcutaneously.	13 months	Safe dengue vaccine is possible.
Luong et al.^Citation40	Vietnam	RCT	March - July 2009	Dengue	Adults & Pediatrics	120		60	CYD-TDV administered subcutaneously.	6 months	Safety and reactogenicity of CYD-TDV were satisfactory and consistent with results from phase I and other phase II studies.
Osorio et al.^Citation41	Laboratory	RCT	N/A	Dengue	6–8-week-old AG129 mice	72 subjects			DENVax	68 days	It is shown to be safe and immunogenic in humans.

Table 2. Key attributes of published research on malaria vaccination.

Author and Year	Country	Study Design	Study Duration	Vector-Borne Disease	Study Population	Sample Size		Vaccine	Follow-up	Findings
						Vaccinated	Control/ Placebo
Datoo et al.^Citation42	Africa	RCT	June 2020 – July 2020	Malaria	Pediatrics	300	150	R21 in Matrix-M administered intramuscularly	12 months	A booster dose of R21/Matrix-M at 1 year following the primary three-dose regimen maintained high efficacy against first and multiple episodes of clinical malaria.
Datoo et al.^Citation43	Africa	RCT	May 2019 – June 2019	Malaria	Pediatrics	300	150	R21 in Matrix-M administered intramuscularly	12 months	R21/MM appears safe and very immunogenic in African children, and shows promising high-level efficacy.
Sirima et al.^Citation44	Africa	RCT	November 2010 – September 2011	Malaria	Pediatrics	926	923	GMZ2 vaccine administered intramuscularly.	6 months	GMZ2 was well tolerated and immunogenic, and reduced the incidence of malaria, but efficacy would need to be substantially improved.
Neafsey et al.^Citation45	Kenya	RCT	March 2007 – November 2014	Malaria	Pediatrics	223	224	RTS, S/AS01 Vaccine administered intramuscularly.	7 years	The RTS, S/AS01 vaccine has greater activity against malaria parasites in pediatrics of age 5 to 17 months.
Rts SC^Citation46	7 countries	RCT	March 2009 – January 2011	Malaria	Pediatrics	5948	2974	RTS, S/AS01 Vaccine administered intramuscularly.	18 months	The vaccine has the potential to make a substantial contribution to malaria control when used in combination with other effective control measures
RTS et al.^Citation47	11 African sites	RCT	March 2009 – January 2011	Malaria	Pediatrics	5949	2974	RTS, S/AS01 vaccines administered intramuscularly	12 months	RTS,S/AS01 could be an important addition to current malaria control in Africa
Moorthy et al.^Citation48	Africa	RCT	July 2002 – December 2002	Malaria	Adults	186	186	DNA ME-TRAP vaccine administered intramuscularly and intradermally.	6 months	DNA/MVA heterologous prime-boost vaccination is safe and highly immunogenic for effector T cell induction in a malaria-endemic area.
Olotu et al.^Citation49	2 countries	RCT	-	Malaria	Pediatrics	223	224	RTS, S/AS01E vaccines administered intramuscularly	4 years	The two formulations of RTS,S were equally safe and immunogenic, and the lyophilized formulation showed similar levels of efficacy
RTS et al.^Citation50	Africa	RCT	December 2009 – January 2011	Malaria	Pediatrics	1462	738	RTS,S/AS01 vaccine administered intramuscularly	12 months3	The RTS,S/AS01 vaccine co-administered with EPI vaccines provided modest protection against both clinical and severe malaria in young infants.
Olotu et al.^Citation51	2 countries	RCT	March 2007 – October 2008	Malaria	Pediatrics	447	447	RTS, S/AS01E vaccines administered intramuscularly	15 months	RTS,S/AS01E confers sustained efficacy for at least 15 months and shows promise as a potential public health intervention against childhood malaria in malaria endemic countries
Asante et al.^Citation52	3 countries	RCT	April 2007 – October 2009	Malaria	Pediatrics	340	171	RTS, S/AS01E vaccines administered intramuscularly	19 months	Vaccine efficacy was consistent with the target put forward by the WHO-sponsored malaria vaccine technology roadmap for a first-generation malaria vaccine.
Leach et al.^Citation53	Africa	RCT	May 2009 – February 2011	Malaria	Pediatrics	8000	4000	RTS, S/AS01 vaccines administered intramuscularly	32 months	The study will provide efficacy and safety data to fulfill regulatory requirements, together with data on a broad range of endpoints that will facilitate the evaluation of the public health impact of the vaccine and will aid policy and implementation decisions.
Agnandji, Lell et al.^Citation54	Africa	RCT	March 2009 – January 2011	Malaria	Pediatrics	3997	2003	RTS,S/AS01 vaccine administered intramuscularly	12 months	The RTS,S/AS01 vaccine provided protection against both clinical and severe malaria in African children.
Guinovart et al.^Citation55	Africa	RCT	August – September 2008	Malaria	Pediatrics	209	208	RTS,S/AS02A vaccine administered intramuscularly	12 months	Contrary to observations in cohort 1, where efficacy against clinical malaria did not wane over time, in cohort 2 the efficacy decreases with time.
Sacarlal et la.^Citation56	Africa	RCT	April 2003 – May 2007	Malaria	Pediatrics	803	802	RTS, S/AS02A vaccines administered intramuscularly	45 months	These results show evidence that RTS, S/AS02A maintained protection during the 45-month surveillance period, and they highlight the feasibility of developing an effective vaccine against malaria.
Kester et al.^Citation57	Bangkok	RCT	-	Malaria	Adults	02	361	RTS, S/AS01B and RTS, S/AS02A vaccines	5 months	RTS, S/A01IB and RTS.S/AS02A were well tolerated and were safe.
Bejon et al.^Citation58	Tanzania	RCT	March 2007 – August 2007	Malaria	Pediatrics	447	447	RTS, S/AS01E vaccines administered intramuscularly	10.5 months	RTS,S/AS01E shows promise as a candidate malaria vaccine.
Abdulla et al.^Citation59	Tanzania	RCT	July 2006 – February 2008	Malaria	Pediatrics	170	170	RTS, S/AS02D vaccines administered intramuscularly	7 months	The use of the RTS,S/AS02D vaccine in infants had a promising safety profile, did not interfere with the immunologic responses to co-administered EPI antigens, and reduced the incidence of malaria infection
Kester et al.^Citation60	South Africa	RCT	-	Malaria	Adults	34	6	RTS, S/AS02A vaccine	10 weeks	The two formulations of RTS,S were equally safe and immunogenic, and the lyophilized formulation showed similar levels of efficacy.
Aponte et al.^Citation61	Africa	RCT	June 1005 – March 2007	Malaria	Infants	107	107	RTS,S/AS02D vaccine administered intramuscularly	3 months	The RTS,S/AS02D malaria vaccine was safe, well tolerated, and immunogenic in young infants.
Bojang et al.^Citation62	The Gambia	RCT	February 1998 – December 1998	Malaria	Adults	131	119	RTS, S/AS02A vaccines administered intramuscularly	15 weeks	RTS,S/AS02 is safe, immunogenic, and is the first pre-erythrocytic vaccine to show significant protection against natural P falciparum infection.

Figure 2. Visualization of risk of bias assessment is generated by robvis tool.⁶⁵

Table 3. Risk of bias assessment for randomized controlled trials.

	Selection Bias		Performance Bias	Detection Bias	Attrition Bias	Reporting Bias
Study	Random sequence generation	Allocation concealment	Blinding of participants and personnel	Blinding of outcome assessment	Incomplete outcome data	Selective reporting	Other bias
Rivera et al.^Citation26	Low Risk	Unclear	Low Risk	Unclear	Low Risk	Low Risk	Low Risk
Kallas et al.^Citation27	Unclear	Unclear	Low Risk	Unclear	Low Risk	Low Risk	Unclear
Barranco-Santana et al.^Citation30	Low Risk	Low Risk	Low Risk	Low Risk	High Risk	Low Risk	Low Risk
B. Guy et al.^Citation31	Unclear	Low Risk	High Risk	Low Risk	Unclear	High Risk	High Risk
Villar, Dayan et al.^Citation32	Low Risk	Low Risk	Low Risk	Low Risk	Low Risk	Low Risk	Low Risk
Capeging et al.^Citation33	Low Risk	Unclear	Low Risk	Low Risk	Low Risk	Unclear	Unclear
Dayan et al.^Citation34	Low Risk	Unclear	Low Risk	Low Risk	Low Risk	Low Risk	Low Risk
Durbin et al.^Citation35	Low Risk	Low Risk	Low Risk	Low Risk	Low Risk	Low Risk	Low Risk
Villar et al.^Citation36	Low Risk	Low Risk	Low Risk	Low Risk	Unclear	Low Risk	Low Risk
Hss, Koh et al.^Citation37	Low Risk	Unclear	Low Risk	Unclear	High Risk	Low Risk	Low Risk
Lanata et al.^Citation38	Low Risk	Low Risk	Low Risk	Low Risk	Low Risk	Unclear	Low Risk
Sabchareon et al.^Citation39	Low Risk	Unclear	Low Risk	Unclear	Low Risk	Low Risk	Unclear
Luong et al.^Citation40	Low Risk	Low Risk	Low Risk	Low Risk	Unclear	Low Risk	Unclear
Osorio et al.^Citation41	Low Risk	Unclear	Low Risk	Low Risk	Low Risk	Unclear	Unclear
Camacho et al.^Citation63	Low Risk	Low Risk	Low Risk	Low Risk	High Risk	Low Risk	Low Risk
Monath et al.^Citation64	High Risk	Unclear	Low Risk	High Risk	High Risk	Low Risk	High Risk
Datoo et al.^Citation42	Low Risk	Low Risk	Low Risk	Low Risk	High Risk	Low Risk	Low Risk
Datoo et al.^Citation43	Low Risk	Low Risk	Low Risk	Low Risk	High Risk	Low Risk	Low Risk
Sirima et al.^Citation44	Low Risk	Low Risk	Low Risk	Unclear	High Risk	Low Risk	Low Risk
Neafsey et al.^Citation45	Low Risk	High Risk	Low Risk	High Risk	Low Risk	Low Risk	High Risk
Rts SC^Citation46	Low Risk	Unclear	High Risk	High Risk	Low Risk	Low Risk	Unclear
RTS et al.4^Citation47	Low Risk	Low Risk	Low Risk	Unclear	High Risk	Low Risk	High Risk
Moorthy et al.^Citation48	Low Risk	Unclear	High Risk	Unclear	High Risk	High Risk	High Risk
Olotu et al.^Citation49	Low Risk	Low Risk	Low Risk	Unclear	Low Risk	Low Risk	Low Risk
RTS et al.^Citation50	Low Risk	Unclear	Low Risk	Low Risk	High Risk	Low Risk	Low Risk
Olotu et al.^Citation51	Low Risk	Low Risk	Low Risk	Low Risk	High Risk	Low Risk	Low Risk
Asante et al.^Citation52	Low Risk	High Risk	High Risk	High Risk	High Risk	Unclear	High Risk
Leach et al.^Citation53	Low Risk	Low Risk	Low Risk	Unclear	Low Risk	Low Risk	Unclear
Agnandji, Lell et al.^Citation54	Low Risk	Unclear	Low Risk	Unclear	Low Risk	Low Risk	Low Risk
Guinovart et al.^Citation55	Low Risk	Unclear	Low Risk	High Risk	Low Risk	Low Risk	Low Risk
Sacarlal et la.^Citation56	Low Risk	Low Risk	Low Risk	High Risk	High Risk	Low Risk	High Risk
Kester et al.^Citation57	Low Risk	Unclear	Low Risk	Unclear	Low Risk	Low Risk	Unclear
Bejon et al.^Citation58	Low Risk	Low Risk	Low Risk	Unclear	Unclear	Low Risk	Low Risk
Abdulla et al.^Citation59	Low Risk	Unclear	Low Risk	Unclear	High Risk	Low Risk	Low Risk
Kester et al.^Citation60	Low Risk	High Risk	High Risk	High Risk	Low Risk	Unclear	High Risk
Aponte et al.^Citation61	Low Risk	Unclear	Unclear	Unclear	Low Risk	Unclear	High Risk
Bojang et al.^Citation62	Low Risk	Unclear	High Risk	Unclear	High Risk	Low Risk	Unclear

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