Efficacy and Effectiveness of Rotavirus Vaccine on Incidence of Diarrhoea among Children: A Meta-analysis

Katayi Mwila-Kazimbaya1,2*, Samuel Bosomprah1,3, Michelo Simuyandi1, Caroline C Chisenga1, Roma Chilengi1,4 and Sody Munsaka2

1Center for Infectious Disease Research in Zambia, Lusaka

2Department of Biomedical Sciences, School of Health Sciences, University of Zambia, Lusaka, Zambia

3Department of Biostatistics, School of Public Health, University of Ghana, Legon, Accra, Ghana

4School of Medicine, University of North Carolina at Chapel Hill, North Carolina, U.S

*Corresponding Author:
Kazimbaya KM
Centre for Infectious Disease Research in Zambia, Lusaka, Department of Biomedical Sciences, School of Health Sciences, University of Zambia, Lusaka, Zambia
Tel: +26 0211 242257-63
E-mail: [email protected]

Received date: January 18, 2018; Accepted date: January 31, 2018; Published date: February 2, 2018

Citation: Kazimbaya KM, Bosomprah S , Simuyandi M, Chisenga CC, Chilengi R, et al. (2018) Efficacy and Effectiveness of Rotavirus Vaccine on Incidence of Diarrhoea among Children: A Meta-analysis. Pediatric Infect Dis Vol.3, No.1:4.doi: 10.4172/2573-0282.100060

Copyright: © 2018 Kazimbaya KM, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

 
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Abstract

Background: Introduction of rotavirus vaccines has resulted in a decrease in rotavirus related mortality and morbidity. We sought to conduct a meta-analysis to estimate the effect of rotavirus vaccine on incidence of diarrhoea.
Methods:
The MEDLINE database was searched through PubMed interface using both textword and subject headings (MeSH). The search strategies were [“rotavirus vaccine effectiveness” or “rotavirus vaccine efficacy” or “rotavirus vaccine eff*”]. The reference lists of the most recent studies identified by the search were checked for additional studies (if not already retrieved). We included both randomised trials and observational studies, which investigated the effect of rotavirus vaccine on incidence of diarrhoea.
Results: There was strong evidence of vaccine efficacy (70%) on incidence of diarrhoea (Pooled risk ratio (pRR)=0.30; 95% confidence interval (CI)=(0.24,0.38); p<0.0001), with much lower vaccine efficacy (63%) in low-middle income countries (LMICs) (pRR=0.37; 95% CI=(56,69); p<0.0001). When restricted to severe diarrhoea outcome, we found 74% vaccine efficacy (pRR=0.26; 95% CI=(0.19,0.24); p<0.0001). For vaccine effectiveness in LMICs, we found 53% vaccine effectiveness (pRR=0.47; 95% CI=(0.36, 0.62); p<0.0001) for 1 dose; 61% effectiveness (pRR=0.39; 95% CI=(0.32, 0.47); p<0.0001) for 2 doses and 72% effectiveness (pRR=0.28; 95% CI=(0.14, 0.56); p<0.0001) for 3 doses.
Conclusion:
Incomplete dose series had lower vaccine effectiveness than vaccine efficacy in LMICs where health system capacity is low. However, a 3-dose series had similar effectiveness to vaccine efficacy, suggesting that a booster dose could present a potential benefit in LMIC.

Keywords

Meta-analysis; Efficacy; Effectiveness; Rotarix; RotaTeq; Rotavirus vaccines

Introduction

Rotavirus associated diarrhoea has been a key contributor to the morbidity and mortality among children under 5 years of age worldwide [1] and low-middle income countries (LMICs) bear the greater burden. This problem has led to the widespread introduction of Rotarix™ (GlaxosmithKline Biologicals, Belgium) and RotaTeq™ (Merck, USA) vaccines into national immunization programmes. As of December 2017, 93 countries have done so at either national, sub-national or began phased introduction of the vaccines [2]. The World Health Organization (WHO) made this recommendation after randomised clinical trials showed efficacy in high income countries (HICs) of between 80-95% [3-6].

Although subsequent trials from low and middle income countries (LMICs) showed much lower efficacy rates between 40 and 60% [7-10], the public health impact in these high burden settings was still compelling enough to continue the immunization campaigns. Several other vaccines are in the developmental and licensure phase such as Rotavin™ and RotaVac™ which have partial or restricted licensure in China, Vietnam and India [11,12]. Rotasil™ is another vaccine currently under development and was recently tested in Niger [13]. All have shown similar vaccine efficacy and effectiveness trends in LMICs [11-14].

Much data on post licensure effectiveness of rotavirus vaccines has been published on HICs which still indicate how well rotavirus vaccines have worked. LMICs researchers are now also beginning to generate more information on vaccine effectiveness in their respective locations that has shown that vaccine responses have continued to be sub-optimal [7-10,15-17].

We will focus on consolidating vaccine efficacy and effectiveness data for globally licensed vaccines Rotarix and RotaTeq in HICs and LMICs as well as some of the steps and areas that still need to be addressed in order to improve vaccine effectiveness in LMICs.

Methods

Search strategy for identification of studies

The MEDLINE database was searched through PubMed interface using both textword and subject headings (MeSH). The search strategies were [“rotavirus vaccine effectiveness” or “rotavirus vaccine efficacy” or “rotavirus vaccine eff*”], which retrieved 858 studies. The reference lists of the most recent studies identified by the search were checked for additional studies (if not already retrieved).

Criteria for including studies for the review

In the efficacy analysis we included randomised clinical trials reporting efficacy of Rotarix (RV1) and RotaTeq (RV5). In the effectiveness analysis we included observational studies reporting population effectiveness of Rotarix (RV1) or RotaTeq (RV5) against hospital admission for rotavirus gastroenteritis (RVGE) or acute gastroenteritis (AGE) for incomplete and complete doses in all countries regardless of whether they are included in national immunisation programmes or privately offered. Duplicates were removed, as were cost effective, genotype specific, impact, methodological and review articles, leaving 68 articles for inclusion in the analysis. Efficacy data included overall efficacy and severe rotavirus related gastroenteritis, whilst effectiveness data included efficacy against hospital admission. All studies published until October 2017 was eligible for inclusion.

Data extraction

Two authors (K.M-K, SB) extracted data from the studies using data extraction form designed to capture relevant data for this purpose and the differences (if any) were reconciled. For the efficacy studies, the measure of effect for the meta-analysis was risk ratio (RR), which measures cumulative incidence more accurately. For studies that reported odds ratio, we recalculated risk ratios by reconstructing the 2×2 tables from data in the original paper because odds ratios usually overestimate risk ratios especially where the incidence of the outcome is common (>10%).

The recalculation was convenient because efficacy studies are required to report the unadjusted result as primary analysis [18]. For the effectiveness studies, we did not recalculate the measure of effect because the primary analysis was adjusted effect. All studies measured diarrhoea severity using Vesikari scores of 11 [19] or Clarke score of 16 [20]. We followed the preferred reporting items for systematic reviews and metaanalysis (PRISMA) in the conduct of this review. Severe diarrhoea was defined as Vesikari score of 11 or greater. Any diarrhoea was defined as mild or moderate or severe.

Statistical analysis

We calculated a weighted average of the effect measures across studies using ‘metan’ command in Stata. Forest plot was also presented. The ‘metan’ command is flexible for any measure of effect because it requires either the frequencies of events in exposed and unexposed group (the approach we used in the efficacy studies) or the logarithm of the effect measure and its standard error (the approach we used in the effectiveness studies). For studies that reported zero events, we replaced the zeros with 0.5 before performing the meta-analysis. For the effectiveness studies, we calculated the standard error of the log-risk ratio or log-odds ratio by back-transforming the relevant confidence intervals as reported in the papers. Studies conducted in different epidemiological settings are likely to vary, so we performed a chi-squared test of heterogeneity.

If there was evidence of heterogeneity, the individual study effect estimates were combined using random effects metaanalysis, which incorporates between-study variability in the weighting. P-values less than 0.05 were considered to show strong evidence of association. Published studies may not be representative of all valid studies undertaken and this can bias meta-analysis. We assessed publication bias using Harbord's modified test for small-study effects [21]. All analyses were performed using Stata 15 MP (StatCorp, College Station, TX, USA).

Results

Overview of included studies

The search identified a total of 858 studies out of which 228 were duplicates (Figure 1). Of the 630 non-duplicated studies, we excluded 98 cost-effectiveness, 67 genotype specific, 13 impact, 21 reviews, and 7 methodological studies leaving a total of 424 studies. After applying the eligibility criteria, we further excluded 357 studies leaving a total of 67 full text articles for analysis out of which 16 were severe RVGE efficacy, 4 overall efficacy, and 47 efficacy against hospital admission studies (Figure 1).

pediatric-infectious-diseases-eligible-trials

Figure 1: Flow diagram for identification of eligible trials.

Characteristics of included studies

27 studies investigated the efficacy of rotavirus vaccine on incidence of diarrhoea, out of which 7 studies investigated the overall efficacy of the vaccines [22-31] while 20 studies investigated efficacy on severe diarrhoea (Table 1) [4,5,31-45]. 23 studies were in LMICs while 4 studies were in HICs contributing a total sample size of 135,486 (Table 1). Data from the HICs included data from multicenter trials that was not disaggregated by country. 13 investigated RV1 and 6 investigated RV5 (Table 1).

Reference Country/Region Demo Vaccine Type Sample Size Loss to Follow Up Study Duration (months) Efficacy Vaccinated No Diarrhoea Vaccinated Diarrhoea Non- Vaccinated No Diarrhoea Non- Vaccinated Diarrhoea
Arajuo et al. [82] Brazil LMIC RV1 2155 1 8 64.5 460 22 130 19
Armah et al. [10] Ghana, Mali and Kenya LMIC RV5 5468 134 17.5 64.2 2712 21 2735 58
Armah et al. [10] Ghana LMIC RV5 5468 134 18.2 65 3255 15 3235 42
Armah et al. [10] Mali LMIC RV5 5468 134 18.2 1 2835 4 2844 4
Armah et al. [10] Kenya LMIC RV5 5468 134 16 83.4 1892 2 1876 12
Bhandari et al. [26] India LMIC Rotavac 4532 101 20 56.3 4298 56 2123 64
Cunliffe et al.[27] Malawi LMIC RV1   9 19 49.7 989 41 445 38
Feikin et al. [33] Kenya LMIC RV5 1308 185 7 83.4 569 2 552 12
Iwata et al. [28] Japan HIC RV5 762 4 7 100 355 0 346 10
Lau et al. [31] China, Hong Kong LMIC RV1 3025   20 100 1494 0 1491 8
Li et al. [32] China LMIC RV1 3333 13 24 75 1567 8 1541 32
Linhares et al. [32] Latin America LMIC RV1 14286 248 20 83.1 7195 10 7023 58
Madhi et al. [94] SA and Malawi LMIC RV1 4939 206 12 61.2 2918 56 1373 70
Madhi et al. [94] South Africa LMIC RV1 973 206 12 81.5 1929 15 928 32
Madhi et al. [94] Malawi LMIC RV1 505 206 12 49.7 989 41 445 38
Mo et al. [35] China LMIC RV5 4040  1  12 78.9 1916 11 1885 52
Phua et al. [29,31] Hong Kong, Singapore and Taiwan HIC RV1 10519 155 21 96.1 5261 1 5205 51
Ruiz-Palacios et al. [4] Latin America LMIC RV1 20169 239 12 84.8 8997 12 8781 77
Sow et al. [22] Mali LMIC RV5 1960 36 12 1 782 41 754 71
Tregnaghi et al. [38] Latin America LMIC RV1 6568 34 7.4 81.6 4204 7 2080 19
Vesikari et al. [101] Europe HIC RV1 3994 23 5.7 95.8 2567 5 1242 60
Vesikari et al. [101] European HIC RV1 3874 23 5.7 95.7 2568 4 1254 48
Zaman et al. [25] Bangladesh and Vietnam LMIC RV5 2036 7 21 51 953 38 907 71
Zaman et al. [25] Bangladesh LMIC RV5   7 21 45.7 953 17 907 31
Zaman et al. [25] Vietnam LMIC RV5   7 21 72.3 953 2 907 7
Zaman et al. [25] Bangladesh LMIC RV1 12318     42.8 5784 53 5066 101
Zaman et al. [25] Bangladesh LMIC RV1 12318 7 24 41.5 5735 102 4995 172

Table 1: Features of studies included in vaccine efficacy analysis

47 studies investigated vaccine effectiveness (Table 2) [5-16,40-77]. 29 studies were from HICs [5,47,48,60-62,72-74,78-84] and 18 were from LMICs (Table 2) [7-16,40-47,50-54,67-79]. 20 studies evaluated RV1, 10 studies evaluated RV5 and 11 studies evaluated the use of either RV1 or RV5. The total sample size across all the studies was 777,809 (Table 2).

Reference Country/ Region Demo Sample Size Vaccine Type
Abeid et al. [52] Zanzibar LMIC 805 RV1
Adlhoch et al. [59] Germany HIC 368 RV1/RV5
Araki et al. [65] Japan HIC   RV1/RV5
Armah et al. [101] Ghana LMIC 657 RV1
Beres et al. [7] Zambia LMIC 529 RV1
Boom et al. [48] USA HIC 205 RV5
Braeckman et al. [45] Belgium HIC 431 RV1
Cardellino et al. [75] Nicaragua LMIC   RV5
Castilla et al. [57] Spain HIC 6792 RV1/RV5
Chang et al. [55] China HIC 1088 RV1
Chang et al. [55 China HIC   RV5
Cortese et al. [44] USA- RV1 HIC 593 RV1
Cortese et al. [44 USA-RV5 HIC 593 RV5
Cotes-Cantillo et al. [42]   Colombia LMIC 974 RV1
de Palma et al. [40] El Salvador LMIC 323 RV1
Desai et al. [63] USA HIC 122 RV1/RV5
Field et al. [72] Australia HIC 459 RV5
Fujii et al. [62] Japan HIC 244 RV1/RV5
Gastanaduy et al. [83] Botswana LMIC 610 RV1
Gastanaduy et al. [83] Guatemala LMIC 1417 RV1/RV5
Gheorgita et al. [85] Moldova LMIC 957 RV1
Gosselin et al. [60] Canda HIC 11203 RV1/RV5
Groome et al. [81] South Africa LMIC 1974 RV1
Ichihara et al. [46] Brazil LMIC 2176 RV1
Justino et al. [54] Brazil LMIC 1045 RV1
Leshem et al. [69] Israel HIC 515 RV5
Marlow et al. [64] Portugal HIC   RV1/RV5
Martinon-Torres et al. [58] Spain HIC 467 RV1/RV5
Mast et al. [71,73] Nicaragua LMIC 1092 RV5
Muhsen et al. [53] Israel HIC 327 RV1
Patel et al. [67] Nicaragua LMIC 975 RV5
Patel et al. [67] Bolivia LMIC 2318 RV1
Payne et al. [68] USA HIC 904 RV1
Payne et al. [68] USA HIC 2961 RV5
Perez-Vilar et al. [80] Spain HIC 174744 RV1
Perez-Vilar et al. [80] Spain HIC 174744 RV5
Pringle et al. [10] Bolivia LMIC 776 RV1
Sehakyan et al. [81] Aremenia LMIC 486 RV1
Snelling et al. [41] Australia HIC 208 RV1
Staat et al.[68] USA HIC 833 RV5
Tate et al. [84] Rwanda LMIC 200 RV5
Tharmaphornpilas et al. [61] Thailand HIC 2893 RV1/RV5
Vesikari et al. [101] Finland HIC 509 RV5
Wang et al. [71] USA HIC 59307 RV5
Wang et al. [71] USA HIC 146237 RV5
Yang et al. [76] Taiwan HIC 201  
Yeung et al. [66] Japan HIC 404 RV1/RV5

Table 2: Features of studies included in vaccine effectiveness analysis.

Vaccine efficacy on incidence of diarrhoea (severe and/or any)

There was evidence of substantial variability between studies (I2=74.4%, p<0.0001) with about 74.4% of the pooled betweenstudy heterogeneity attributable to the variability in the true effect (Figure 2A). There was strong evidence of vaccine efficacy (70%) on incidence of diarrhoea (Pooled risk ratio (pRR)=0.30; 95% confidence interval (CI)=(0.24, 0.38); p<0.0001) (Figure 2A).

pediatric-infectious-diseases-income-countries

Figure 2a: Efficacy of rotavirus vaccine on incidence of diarrhoea (severe and any) by country income status. ES represents the estimated risk ratio, I2 is a measure of heterogeneity between studies. LMIC represents low and middle income countries and HIC represents high income countries. RV1=Rotarix and RV5=RotaTeq.

When stratified by country income status, we observed strong evidence of vaccine efficacy (96%) in HICs (pRR=0.04; 95% CI=(93, 98); p<0.0001) while an efficacy of 63% was observed in LMICs (pRR=0.37; 95% CI=(56, 69); p<0.0001) (Figure 2A). We observed evidence of publication bias in terms of small-study effect (bias=-2.55; Harbord’s modified test p=0.017) (Figure 2B). When restricted to severe diarrhoea as the outcome, we also found strong evidence of vaccine efficacy (74%) (pRR=0.26; 95% CI=(0.19,0.24); p<0.0001) (Figure 3). For any diarrhoea outcome, the efficacy was 53% (pRR=0.47; 95% CI=(0.36,0.60); p<0.0001) (Figure 4).

pediatric-infectious-diseases-efficacy-studies

Figure 2b: Funnel plot assessing small-study effect for the vaccine efficacy studies.

pediatric-infectious-diseases-efficacy-studies

Figure 3: Efficacy of rotavirus vaccine on incidence of severe RVGE by country income status. ES represents the estimated risk ratio, I2 is a measure of heterogeneity between studies. LMIC represents low and middle income countries and HIC represents high income countries. RV1=Rotarix and RV5=RotaTeq.

pediatric-infectious-diseases-middle-income

Figure 4: Efficacy of rotavirus vaccine on incidence of any diarrhoea by country income status. ES represents the estimated risk ratio, I2 is a measure of heterogeneity between studies. LMIC represents low and middle income countries and HIC represents high income countries. RV1=Rotarix and RV5=RotaTeq.

In a secondary analysis to assess the efficacy of specific vaccine type, we found similar results. RV1 showed an efficacy of 76% (pRR=0.24; 95% CI=(0.17, 0.33) while RV5 showed an efficacy of 60% (pRR=0.40; 95% CI=(0.31, 0.53) (Figure 5).

Vaccine effectiveness on incidence of diarrhoea

In assessing the effect of rotavirus vaccine in real world setting, we found strong evidence of about 78% reduction in incidence of diarrhoea due to the vaccine (pRR=0.22; 95% CI=(0.18, 0.28); p<0.0001).

pediatric-infectious-diseases-risk-ratio

Figure 5: Vaccine efficacy by vaccine type. ES represents the estimated risk ratio, I2 is a measure of heterogeneity between studies. LMIC represents low and middle income countries and HIC represents high income countries. RV 1=Rotarix and RV5=RotaTeq.

This effect was influenced by the number of vaccine doses; we observed that as the number of dose increases so does the vaccine effectiveness (Figures 6A-6C). For 1 vaccine dose, the vaccine effectiveness in LMIC was 53% (pRR=0.47; 95% CI=(0.36, 0.62); p<0.0001) (Figure 6A). For 2 doses, the effectiveness in LMIC was 61% (pRR=0.39; 95% CI=(0.32, 0.47); p<0.0001) (Figure 6B). For 3 doses, the effectiveness in LMIC was 72% (pRR=0.28; 95% CI=(0.14, 0.56); p<0.0001) (Figure 6C).

pediatric-infectious-diseases-income-countries

Figure 6a: Vaccine Effectiveness analysis by Income status for 1 Dose of Vaccine. ES represents the estimated risk ratio, I2 is a measure of heterogeneity between studies. LMIC represents low and middle income countries and HIC represents high income countries. RV1=Rotarix and RV5=RotaTeq.

pediatric-infectious-diseases-income-countries

Figure 6b: Vaccine Effectiveness analysis by Income status for 2 Doses of Vaccine. ES represents the estimated risk ratio, I2 is a measure of heterogeneity between studies. LMIC represents low and middle income countries and HIC represents high income countries. RV1=Rotarix and RV5=RotaTeq.

pediatric-infectious-diseases-income-countries

Figure 6c: Vaccine Effectiveness analysis by Income status for 3 Doses of Vaccine. ES represents the estimated risk ratio, I2 is a measure of heterogeneity between studies. LMIC represents low and middle income countries and HIC represents high income countries. RV1=Rotarix and RV5=RotaTeq.

Discussion

Results from both the efficacy and effectiveness trials show that rotavirus vaccines have been effective in reducing the scourge of rotavirus associated diarrhoea. Our analysis was able to consolidate data that shows HICs have consistently higher efficacy and effectiveness rates than LMICs; and is true for both RV1 and RV5.

Effectiveness data from real world setting results have also indicated that incomplete vaccine series are able to provide some protection to infants though to a lesser extent than a complete series. The incomplete series had a much lower effectiveness in LMIC than vaccine efficacy in LMIC. Incomplete series is common in LMICs where inadequate health facilities and long distances to health facilities exist. We found that a 3- dose vaccine series had effect similar to vaccine efficacy in LMIC, making it a logical argument for a booster dose especially in LMICs.

Improved vaccine effectiveness: Terrain à forte

The differences in efficacy and effectiveness in HICs and LMICs however still remain the main discussion point as there is need for further reduction in rotavirus associated mortality and morbidity [85]. Various factors have been postulated as contributing to this observed effect. Host factors such as genetics, malnutrition, enteric environmental dysfunction (EED), maternal factors such as antibodies passed onto the infant, various components of breast milk, exposure to HIV and other environmental factors including poor sanitation, concurrent infection with other pathogens have all been postulated to influence vaccine effectiveness [86-97].

Another factor postulated to possibly have an effect is strain diversity in HICs and LMICs. Both RV1 and RV5 are vaccines originally designed by HIC researchers from strains present in HIC regions. However, research has indicated that the vaccines are not strain specific but cross-cutting without evidence of vaccine induced selection pressure [43,98,99]. Nonetheless, the increased strain diversity being observed in many LMICs requires seroepidemiological vigilance to ensure tracking of any emerging strains such as P[4]G2 that may account for reduced efficacy through limited cross protection [100-104].

Despite greater understanding of contributing factors to reduced vaccine efficacy, we are faced with the fact that a lot of these factors are almost impossible to resolve. The high maternal immunity that is passed onto the child is a consequence of where one lives and poor water, sanitation and hygiene (WASH) that cannot easily be changed. Unless this is addressed, mothers will continue to pass these, on to their infants. The same applies to the EED; in order to change the micro biome that exists in individuals, it will require interventions that address which organisms are first introduced into the system. Additionally in low income settings with low availability of funds, the use of formula is not a feasible solution to address the issue of maternal antibodies passed onto the child during breast feeding.

Genetic makeup has also been included in the list of factors affecting vaccine effectiveness. Despite advances in science, genetics is still a growing area and we have not yet reached a point where we can change ones genetic code if one is predisposed towards a disease even in the developed settings. Thus, genetic predisposition is another unsolvable in the quest for better vaccine effectiveness. Another key area is that of mal(nutrition) in LMICs. Again, despite great efforts being made worldwide, the magnitude of this problem renders it unsolvable for years to come. Unless we can find a world in which all children are able to have sufficient food and the right kind of food, this too shall remain a hindrance to our efforts to obtain better vaccine effectiveness.

Future perspectives

Despite the many hindrances to achieving better vaccine effectiveness in LMICs there are still many other areas that are available to work on. The next generation of vaccines can be targeted to areas that maybe within our control such as alternative routes of administration; short course full dose regimen. The ease of use and lower cost of oral vaccines is the main reason for their inclusion in national immunisation programmes. However, the large number of interfering factors has led us to reassess their use. As is the case with Polio, we may have to go the parenteral route to effectively circumvent the problems encountered via the oral route [105].

Another way of dealing with interference is the adjustment of the vaccine schedule; a neonatal dosing schedule has been proposed as potentially beneficial to improved vaccine immunogenicity [106,107]. A booster dose has also been proposed as viable option for enhanced vaccine immune responses of current vaccines in use [108]. While use of the expanded programme on immunization (EPI) was recommended in order to reach as many infants as possible, there may be larger benefits in offering immunization options outside of this schedule. This could be in the form of changing the time to one at which maternal antibodies are waning or as early as possible to ensure adequate protection from early exposure. Nonetheless, these options need to be weighed against the challenge of low coverage in LMIC [109], when venturing outside of the EPI.

Lastly, use of effective adjuvants has not been fully explored in rotavirus immunology [110]. This is particularly key when considering neonates in whom the immune system is naïve [111,112]; and yet it’s a practical window to beat the early exposure of infants to pathogens [88].

Conclusion

While current rotavirus vaccines have saved many lives in LMIC settings, there are still clear gaps in vaccine performance. This paper has comprehensively shown the differences and need for concerted effort to improve vaccine performance in these areas where in fact, vaccines are most needed.

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