REVIEW

Vaccine Hesitancy as a Challenge or VaccineConfidence as an Opportunity for ChildhoodImmunisation in India

Ashish Agrawal . Shafi Kolhapure . Alberta Di Pasquale .

Jayant Rai . Ashish Mathur

Received: April 23, 2020 / Published online: May 23, 2020� The Author(s) 2020, Corrected publication 2020

ABSTRACT

Vaccines have contributed substantially todecreasing the morbidity and mortality rates ofmany infectious diseases worldwide. Despitethis achievement, an increasing number ofparents have adopted hesitant behaviourstowards vaccines, delaying or even refusingtheir administration to children. This hasimplications not only on individuals but alsosociety in the form of outbreaks for e.g. measles,chicken pox, hepatitis A, etc. A review of theliterature was conducted to identify the

determinants of vaccine hesitancy (VH) as wellas vaccine confidence and link them to chal-lenges and opportunities associated with vacci-nation in India, safety concerns, doubts aboutthe need for vaccines against uncommon dis-eases and suspicions towards new vaccines wereidentified as major vaccine-specific factors ofVH. Lack of awareness and limited access tovaccination sites were often reported by hesi-tant parents. Lastly, socio-economic level, edu-cational level and cultural specificities werecontextual factors of VH in India. Controversiesand rumours around some vaccines (e.g.,human papillomavirus) have profoundlyimpacted the perception of the risks and bene-fits of vaccination. Challenges posed by tradi-tions and cultural behaviours, geographicalspecificities, socio-demographic disparities, thehealthcare system and vaccine-specific featuresare highlighted, and opportunities to improveconfidence are identified. To overcome VH andpromote vaccination, emphasis should be onimproving communication, educating the newgeneration and creating awareness among thesociety. Tailoring immunisation programmes asper the needs of specific geographical areas orcommunities is also important to improve vac-cine confidence.

Digital Features To view digital features for this articlego to https://doi.org/10.6084/m9.figshare.12220523.

A. Agrawal (&)Medical Affairs Department, GSK, Hyderabad, Indiae-mail: ashish.8.agrawal@gsk.com

S. KolhapureMedical Affairs Department, GSK, Mumbai, India

A. Di PasqualeMedical Affairs Department, GSK, Wavre, Belgium

J. RaiMedical Affairs Department, GSK, Lucknow, India

A. MathurPrivate Practitioner, 4-Kabir Marg, Lucknow, India

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https://doi.org/10.1007/s40121-020-00302-9

Keywords: Immunisation; India; Vaccination;Vaccine confidence; Vaccine hesitancy

Key Summary Points

Rumours and controversies aroundvaccine safety have shed light on thestrong presence of parental vaccinehesitancy (VH) in India.

A literature review identifies challenges toovercome VH as well as opportunities toimprove vaccine confidence.

Vaccine-specific causes (e.g., cost, safetyconcerns), individual (e.g., doubts aboutneed to vaccinate, lack of confidence invaccination programmes) and contextual(e.g., religion, traditions) influences areinvolved in parental VH.

Healthcare workers and other healthactors have a crucial role in improvingconfidence towards childhoodvaccination by communicating accurateinformation about risks and benefits ofvaccines to parents.

Educating, creating awareness andtailoring immunisation programmes foreach vaccine are proposed avenues toimprove parental confidence invaccination.

INTRODUCTION

Public concerns about vaccines are as old asvaccines themselves, ranging from safety con-cerns to doubts about the needs for vaccination[1]. The internet has enhanced opportunities foranti-vaccine people to connect, organise andincrease their share of voice at global level. As aresult, the antivaccine community has suc-ceeded in influencing individual’s behaviour

Fig. 1 Plain language summary

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and lowering confidence in vaccination despiteits proven effectiveness [2].

Thus, in recent years, attention has grownaround the behaviour of individuals rangingfrom those who are total acceptors to those whoare complete refusers, i.e., hesitant to take vac-cines [3]. Refusing or delaying vaccination con-tributes to gaps in vaccine uptake andimmunisation coverage—a significant factor incontrolling or eliminating vaccine pre-ventable diseases (VPDs). Thus, vaccine hesi-tancy (VH) is not only a threat to elimination ofVPDs (e.g.,measles, polio, etc.) but is also amajorfactor contributing to re-emergence of such dis-eases. There may be multiple factors stimulatingVH, depending on the context, individuals andspecific features of the vaccines [3, 4]. Aside fromaddressing these factors, improving vaccineconfidence through better communication, byhealth authorities as well as by the scientific andpharmaceutical communities, may help tocounteract VH [5–7]. The World Health Organi-sation (WHO) listed VH among the top tenthreats to global health in2019 [8].WHOdefinedVH as ‘‘(…) delay in acceptance or refusal of vac-cines despite availability of vaccination services.Vaccine hesitancy is complex and contextspecific, varying across time, places and vaccines.It is influenced by factors such as complacency,convenience and confidence’’ [3].

India, as a country, has the largest birthcohort in the world, with 27 million childrenborn each year. It has not been able to reach thegoal of 90% coverage for all vaccines includedin national immunisation schedule because ofvarious factors including VH [9, 10]. To controlVPD, it is crucial to achieve high vaccinationrates—this can be achieved by countering anti-vaccination messages and by increasing publicconfidence in vaccines [11–13]. It also appearskey to develop campaigns that address theconcerns faced by individuals hesitant to vac-cinate themselves or their children [14–16].

The objective of this qualitative literaturereview was to identify (1) the set of VH deter-minants impacting childhood immunisation inIndia, (2) key challenges to overcoming reluc-tance to vaccination in the country and (3)major opportunities to minimise VH in Indiaand increase confidence around vaccination.

LITERATURE SEARCH

First, a literature search was conducted inPubMed for research articles with ‘‘hesitancy’’[All Fields] AND ‘‘India’’ [All Fields] over the2015–2019 period and in Embase for additionalarticles published during the same period usingthe following search equation: (‘vaccine hesi-tancy India’ OR ((‘vaccine’/exp OR vaccine)AND hesitancy AND (‘India’/exp OR India))).Only articles reporting results from a quantita-tive or qualitative survey about VH in Indiawere included. The search for VH determinantswas complemented by narratives about recentvaccine-related controversies as well as a selec-tion of challenges and opportunities relevant tothe Indian context.

Furthermore, this article is based on previ-ously conducted studies and does not containany studies performed by any of the authorswith human participants or animals.

DETERMINANTS OF VH IN INDIA

After exclusion of the articles not related tovaccination or focused on adult/traveller vacci-nation, nine articles reporting childhood VHdeterminants in India were retrieved [17–25].Seven of them reported results from surveys orinterviews of parents/caregivers in India[18–21, 23–25]. One study mixed a cross-sec-tional survey with interviews of parents andhealthcare workers [17]. One article presentedchallenges reported by healthcare providersfrom different countries including India [22].Among those nine articles, one reported resultsfrom the pulse polio campaign [18], and twowere specific to measles-rubella (MR) vaccina-tion [17, 19]. It was important to identify notonly factors that add to VH in these articles butalso factors that add to confidence in vaccina-tion. Figure 1 elaborates on the findings in aform that can be shared with patients byhealthcare professionals (HCPs) and Fig. 2summarises the major factors that lower orimprove vaccine confidence.

Social connections affect attitudes towardsvaccination, as seen during the oral polio vac-cination campaign [18]. Among the 1355

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households with one or more children\5 yearsold, 1074 (79.3%) accepted vaccination, while137 were hesitant (10.1%) and 144 (10.6%)refused vaccination. Vaccine-refusing house-holds had 189% more ties to other vaccine-re-fusing households than to vaccine-acceptinghouseholds, which shows a clustering of VHcommunities.

Influence of social relationships and accessto information through social media had animpact on the status of MR vaccination [19].Vaccine acceptance was higher when offered atschool (P\ 0.001). It was also high amongparents who trusted school teachers (P\ 0.003)and other school children (P\ 0.014) as sourcesof information. However, acceptance was loweramong parents who trusted information fromsocial media (P B 0.036).

In another study, 14.1% of the 461 parents ofchildren between 9 months and 15 years oldwere VH towards the MR campaign [17].Mothers[30 years old were found to be 2.65times more prone to VH than younger ones(P\0.001). Employed mothers were moreprone (P\ 0.001) to VH than unemployedmothers. VH was also more prevalent in parentswith less education (P B 0.04) than in thosewho had graduated. Major hindering factorswere inadequate knowledge about the vaccina-tion campaign, rumours about the safety of thevaccine, sudden planning and under-prepared-ness at the health system level. A major facili-tating factor for the campaign was the roleplayed by healthcare professionals in spreading

awareness and increasing trust in vaccines andvaccination.

A large-scale survey (n = 20 749) was con-ducted to understand the dynamics of vaccineconfidence in five countries, including India[25]. In the latter sub-group of households withchildren\5 years old (n = 288/1 259), 36respondents (12.5%) were found hesitanttowards vaccination, among which 6 firmlyrefused vaccination for their children. A total of42 reasons were provided by these 36 respon-dents: 13 related to confidence (safety concerns,lack of effectiveness, bad experience with vac-cination or HCP or healthcare facility, preferreduse of traditional medicine, religious reasons), 1to complacency (vaccine not needed), 7 toconvenience (lack of time, remoteness, vaccineshortage) and 21 to other factors (e.g., baby criesor has problems, not communicated/don’tremember). Of the 21 latter factors, ‘‘baby criesor has problem’’ could have been classified into‘‘confidence’’.

In another study, only 17% (33/194) of thechildren\5 years old in households located inthe slums of Siliguri had received vaccinationson time [23]. Reluctance to vaccinate (26.1%)and unawareness/receiving no reliable infor-mation (20.5%) were the major reasons cited forVH. Nuclear families and\ 5 years schooling ofthe mother had higher odds of VH.

A comparison of VH across five low- andmiddle-income countries, including India,made using the WHO’s 10-item VH Scale, waspublished [21]. The VH data for India werecollected between 2017 and 2018 from 309

Fig. 2 Factors negatively (red) and positively (green) influencing vaccine confidence in India

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mothers of children\ 5 years old. The majorityof the hesitant mothers were concerned aboutsafety (39.2%), believed some vaccines were nolonger needed (33%) or feared that newlyintroduced vaccines could threaten children’shealth (20%). Maternal concerns about theadverse effects of vaccines, including newlyintroduced ones, were found at varying degreesin these five countries. No consistent associa-tion between education and VH was noted. Atthe same time, among all surveyed participantsin Bangladesh, China, Ethiopia, Guatemala andIndia, a large majority perceived that vaccinesare important for their child’s health (95%),that vaccines are effective (93%) and that vac-cines can protect their child (94%).

In 2018, interviews at a tertiary care centre of150 mothers of children 1 to 5 years oldrevealed that suspicions towards newer vaccines(61.4%), concerns about adverse events (90.7%)and perception that vaccines are not necessaryfor uncommon diseases (85.3%) were related tohesitant behaviour as measured by the vaccineconfidence index [20, 25]. Mothers’ educationwas seen to protect against VH, whereas father’seducation, father’s use of social media andreliance on sources of information other thanHCP increased the risk of VH.

A qualitative survey was conducted among75 HCPs from four countries (UK, USA, Ger-many, India) in 2018 [22]. Challenges theyfaced were found similar (i.e., low patient-levelvaccine knowledge, patient miseducation,untimely vaccine information, frequentlychanging schedules, pressure to achieve vacci-nation targets, vaccine costs). The ten Indianpaediatricians interviewed reported that vaccinecosts and shortages were important challengesin India. They also regret the lack of generalunderstanding about the purpose of vaccines insegments of the population.

A questionnaire based on that created by theWHO strategic advisory group of experts onimmunisation was also administered to 260households (Balangir: 180; Nuapada: 80) inOdisha [24]. Nearly 85% had monthly incomes\5000 Indian rupees (75 US dollars). Almost allknew that vaccines protect against infectiousdiseases and that parents should vaccinate theirchildren. Around 10% highlighted long travel

distances as important barriers to vaccineuptake. Nearly 28% and 9% of parents inBalangir and Nuapada, respectively, had heardnegative information about the vaccines. Still,[75% of them had their children vaccinated.

CHALLENGES SURROUNDINGVACCINE HESITANCYOR CONFIDENCE IN INDIA

Many challenges surround vaccination in Indiaand need to be addressed. However, some areparticularly prominent because of their impactor shared roots with broader health issues.

Rumours and Controversies

Several controversies and false informationhave negatively impacted vaccine confidenceover the last 20 years. During poliomyelitisvaccination programmes in early 2000, a seed ofdistrust was sown in particular communities bylinking vaccination with sterility and by falselyclaiming that pig’s blood was present in thevaccine, among other things [26, 27]. However,realising the importance of vaccination, reli-gious leaders who were silent initially, alongwith community influencers, eventuallyactively fostered the social mobilisation that ledto the successful elimination of poliomyelitis[28, 29].

Safety concerns of a severe nature were raisedafter the deaths of seven girls during twohuman papillomavirus (HPV) studies conductedin 2010 [30, 31]. An enquiry committee inves-tigated the controversial cases and concludedthat the vaccines were not responsible for thedeaths [32]. Vaccination against HPV has thepotential to provide great benefits for theIndian population as cervical cancer, which ismainly caused by persistent HPV infection, isthe second most common cancer in Indianwomen [33]. Nevertheless, the call for intro-duction of HPV vaccine is still opposed despiterecommendation by the Indian Council ofMedical Research and the National TechnicalAdvisory Group on Immunisation [34].

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The decision to introduce Haemophilusinfluenzae type B (Hib) containing pentavalentvaccines in the universal immunisation pro-gramme in 2009 is yet another example ofchallenges regarding the need and risk-benefitratio of vaccines. In this case, questions wereraised based on studies suggesting lower burdenof Hib meningitis in Indian children than inother parts of the world and based on the sug-gestion—that use of the pentavalent vaccineshad low value to children’s health [35]. Basedon available evidence, concerns were found tobe unsubstantiated and the government even-tually introduced the pentavalent vaccines in2011 [35, 36].

Social Interactions

Behaviour with respect to vaccination tends todepend on who you know, where you live orboth. For example, low uptake of the MR vac-cine (44% of the targeted number of children)during the 2017 vaccination campaign in TamilNadu [19] reflects the hesitant behaviour ofparents associated with safety concerns that areusually spread through social interaction andmedia.

Healthcare System and Access to Facilities

India has various geographical features withareas that are either densely or sparsely popu-lated. In 2012, only 37% (versus 73%) and 68%(versus 92%) of people living in rural (versusurban) areas were able to access inpatient hos-pitalisation and outpatient facilities, respec-tively [37]. Results from pooled, nationallyrepresentative surveys covering 1998–2008 evi-denced that lack of access to immunisationfacilities, along with absence of healthcareworkers, and ignorance of the place and timingfor getting vaccination were among the reasonsfor delayed or missed vaccination [38]. Strongreductions of urban versus rural disparities infull vaccination rates from 2008 to 2013 arehowever noteworthy [39]. This is possibly dueto the activation of primary health centres,subcentres and community health workers(Anganwadi workers) in rural areas [40].

Contrarily, precarious populations living inurban slums have been found to lack awarenessabout immunisation benefits and experiencedifficulties in accessing healthcare services[41, 42]. Lack of access to healthcare facilitiesand awareness are reasons for the low vaccina-tion rates observed in the poorest strata of theIndian population [40, 42]. Lack of adequateworkforce observed in both public and privatesectors negatively impacts the healthcare stan-dards and thereby the general trust of the pop-ulation in the healthcare system [43].Inadequate workforce increases the pressure onhealthcare workers and may lower their avail-ability for discussing parent’s concerns regard-ing vaccination. Previous negative experiencewith HCPs was indeed reported as one of thereasons for VH [25], and healthcare workers’lack of empathy in slums (possibly due to ele-vated workloads) was perceived as a barrier inthe immunisation process [44].

Economic Factors

The community-based cross-sectional studyconducted in Mumbai, one of the world’s mostpopulous cities, identified the loss of dailyincome as one of the most frequently reportedfactors for missing childhood immunisation inslum areas [44]. The cost of vaccines and vac-cination is a challenge, as very few are offeredfree or as part of the national immunisationprogramme [22]. Nevertheless, VH is alsoobserved in populations with higher socio-eco-nomic statuses and education levels [45].

Vaccine-Specific Challenges

Vaccination schedules are designed in a waythat several vaccines are administered con-comitantly to improve compliance and cover-age. However, due to overcrowding ofvaccination schedules, HCPs and parents haveconcerns to administer several vaccines during asingle visit [46]. Additionally, suspicionstowards newly introduced vaccines, as well asdoubts about the need to vaccinate againstdiseases that are uncommon, are recurrentlyreported in the Indian population [20, 21, 23].

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OPPORTUNITIES TO INCREASEVACCINE CONFIDENCE IN INDIA

Some of the above-mentioned challenges comewith opportunities to address VH and increaseconfidence in vaccination and the health sys-tem. Moreover, identification of determinantsof VH allows tailoring of immunisation pro-grammes, campaigns and policies. Tailoringimmunisation programmes has proven efficientto address gaps in vaccine uptake among pop-ulation, notably by addressing VH [47–49].Here, we present some leads that we believe areworthy to address VH in India.

Communication

Media can have a tremendous influence onpublic opinion, with long-lasting impacts [50].Today, access to social media (72.9% of house-holds use smartphones) is far greater in Indiathan access to TV (45.0%) or cooking gascylinders (21.6%) [18]. Usually, mothers seekinformation online, especially when concernedabout vaccine safety [51]. As it is difficult tocontrol and verify all the information availableon the various platforms, it is important toincrease access to transparent and scientificallyvalidated information about the risks and ben-efits of vaccines as well as answer questions withbalanced and accurate information.

There is a global realisation that publichealth communicators need to adapt theircommunication in a way to improve trust invaccines and vaccination [51–53]. Some pro-posed strategies go even one step further, sug-gesting to focus vaccine communication on thepositive, emotional values of immunisationsrather than limiting it to the scientific content[5, 6].

Healthcare workers remain the most trustedadvisors among all possible sources of reliableinformation when it comes to vaccination[54, 55]. In that regard, and in light of the fac-tors of VH reported in the literature search,availability and preparedness of healthcareworkers for discussing vaccination are of primeimportance. Some paediatricians are alreadyengaged in improving vaccine confidence

through the publication of scientifically accu-rate blogs with the potential to reach a broadaudience [56]. The situation in low- and middle-income countries is even more closely impactedby the healthcare workers (i.e., including com-munity health workers, Anganwadi workers,auxiliary nurse midwifes and health assistants),as they represent the frontline of vaccinationand are often confronted with questions fromhesitant parents [57–59]. Therefore, communi-cation training of healthcare workers appears tobe one of the most promising strategies to dealwith VH and improve vaccine confidence [59].For example, applying the CASE (Corroborate,About Me, Science, and Explain/Advise)approach could help them establish a dialoguewith parents [60]. This approach could evenreinforce the impact of self-help groups that arealready shown to improve healthcare access andawareness in rural communities [61].

Similarly, religious leaders should also beincluded as important partners when commu-nicating about immunisation as they can have amajor impact when supporting it [62]. Forexample, the mobilisation of Muslim leaders inIndia was instrumental in the eradication ofpoliomyelitis [28].

These opportunities around communicationmight help overcome some of the above-men-tioned challenges posed by the cultural contextof India as well as by the behaviour of health-care workers and parent’s due to safetyconcerns.

Education and Creating Awareness

Educating and creating awareness aboutimmunisation and fostering critical thinking onassociated risks and benefits could have atremendous impact on overcoming hesitantbehaviour in a population [63]. Such anapproach has proven advantageous in a differ-ent context, i.e., reduced use of polluting fire-crackers during the Diwali festival [64, 65].Including a basic curriculum on VPDs inschools could also have a positive impact in thelong term by making the new generation awareof vaccination’s risks and benefits (e.g., HPV)[66, 67]. Moreover, school teachers are

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recognised as a trustworthy source of informa-tion by parents accepting vaccination [19].Schools and school teachers should therefore beengaged in vaccination campaigns as theyembody knowledge to the population and alsohave the potential to dissipate cultural barriers,which are a deterrent to vaccination.

Addressing Safety Concerns

Aside from their potential to mitigate parents’safety concerns about multiple vaccine injec-tions during a single visit, combination vacci-nes have economic value by reducing thenumber of injections and inherent administra-tion and stocking costs [68, 69]. In India, thecurrent schedule includes the pentavalentcombination vaccine against diphtheria-per-tussis-tetanus (DTP), hepatitis B (HepB), Hiband a separate polio vaccination, with either thelive attenuated oral vaccine (OPV) or the inac-tivated injected vaccine (IPV) [70]. The use of anavailable hexavalent vaccine against these sixdiseases (DTP-HepB-Hib-IPV) could alleviate thebarriers posed by parents’ fear of pain andadverse effects of vaccination. This would alsofoster the switch from OPV to IPV as the risk of avaccine-derived poliovirus outbreak exists whenusing OPV [71, 72]. As already mentioned, thebenefit of these recommendations should betransparently communicated from a publichealth and an economic perspectives. Assess-ments of the value and risk of the vaccines areimportant aspects for the perception of anyvaccine. Therefore, nurturing and using thenational surveillance programme of adverseevents following immunisation is of primeimportance for building evidence about vaccinesafety and assuring the public that continuousmonitoring is in place to help assessing anysuspicion of safety issue [73].

SUMMARY

Immunisation has been one of the key inter-ventions that has not only reduced morbidity ormortality of some diseases [10], but also has ledto eradication of small pox and now puts polioon the verge of eradication [72, 74]. Despite

these achievements, there are growing concernswith respect to vaccination acceptance amongthe general population, which is largely drivenby lack of vaccine confidence or VH.

VH has notably been attributed to factorssuch as safety [17, 19–21, 23–25]; rumours andcontroversies (e.g., vaccination leads to infer-tility) [17, 26, 27]; lack of awareness aboutbenefits of vaccines [19–25]; influence of stake-holders (e.g., local leaders) in shaping percep-tions among the general population[19, 24, 26]; costs [22]; temporal and geographicbarriers [23–25]; and personal attributes[17, 19, 20, 23, 25].

To address the problem of VH in India, thereis a need to estimate its root causes, formulatecontext-specific strategies relevant to the localsettings and thus help in restoring trust leadingto increased confidence in vaccination. The lit-erature revealed a diversity of settings, some-times revealing conflicting results about theanalysed factors of VH (e.g., the level of educa-tion), further highlighting the context-specificnature of VH in India. The proposed strategiesinclude the involvement of local stakeholders;encouraging the use of different mass mediatechniques to increase awareness of risks andbenefits and address the prevalent myths aboutvaccines and vaccination; improving conve-nience and accessibility to the vaccines;employing reminder and follow-up services;organising training sessions for healthcareworkers to enhance their communication skillsand ability to engage in balanced and scientifi-cally validated dialogues with parents; provid-ing nonfinancial incentives to immunisedindividuals. The success of the polio campaignthat helped in its elimination in India can beattributed to all the above factors and couldserve as an example for overcoming challengesin vaccination.

The issue of VH in India is vast, complex andcould not be exhaustively covered in one paper.The literature search focused on VH regardingchildhood vaccination resulted in the retrievalof few studies specific to it. However, we areconfident that they provide useful insight intothe contemporaneous concerns surroundingvaccines and vaccination in the Indian popu-lation. Also, the present literature review

428 Infect Dis Ther (2020) 9:421–432

focused on identifying the major drivers of VHand ways to leverage these for increasing vac-cine confidence.

As illustrated by the paucity of publisheddata about VH or Confidence determinants inIndia and the recognised challenges surround-ing vaccination, further research is needed. Afirst important step would be the identificationof VH as well as vaccine confidence its measureacross India. Survey tools could help to conductqualitative or quantitative studies in areas oflow vaccine uptake and implement strategies toincrease vaccine confidence. Nevertheless, thepresent study provides a picture of the breadthof knowledge about VH determinants in India,identifies challenges and opportunities toimprove confidence. The collective use of theidentified opportunities seems key to help turnvaccines into vaccination in India.

ACKNOWLEDGEMENTS

Funding. GlaxoSmithKline Biologicals SAfunded this review and all costs associated withits development and publication. All authorshad full access to all of the data in this studyand take complete responsibility for the integ-rity of the data and accuracy of the dataanalysis.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole and have given theirapproval for this version to be published.

Medical Writing, Editorial and OtherAssistance. The authors thank Business &Decision Life Science platform for editorialassistance and manuscript coordination onbehalf of GSK. Benjamin Lemaire coordinatedpublication development and editorial support.Jonathan Ghesquiere provided medical writingsupport. Editorial support and medical writingassistance were funded by GlaxoSmithKlineBiologicals SA. The authors also thank the

reviewers who have helped improve the qualityof the present review manuscript.

Disclosures. Ashish Agrawal is an employeeof the GSK group of companies and declare nonon-financial conflicts of interest. Alberta DiPasquale and Shafi Kolhapure are employees ofthe GSK group of companies, hold shares as partof their employee remuneration and declare nonon-financial conflicts of interest. Jayant Rai,who was an employee of the GSK group ofcompanies during the conduct of the study, iscurrently employed by the Department ofPharmacology, Government Institute of Medi-cal Sciences, Greater Noida, India, and declaresno non-financial conflicts of interest. AshishMathur declares no financial or non-financialconflicts of interest.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any studies performed byany of the authors with human participants oranimals.

Data Availability. Data sharing is notapplicable to this article as no datasets weregenerated or analysed during the current study.

Open Access. This article is licensed under aCreative Commons Attribution 4.0 Interna-tional License, which permits use, sharing,adaptation, distribution and reproduction inany medium or format, as long as you giveappropriate credit to the original author(s) andthe source, provide a link to the CreativeCommons licence, and indicate if changes weremade. The images or other third party materialin this article are included in the article’sCreative Commons licence, unless indicatedotherwise in a credit line to the material. Ifmaterial is not included in the article’s CreativeCommons licence and your intended use is notpermitted by statutory regulation or exceeds thepermitted use, you will need to obtain permis-sion directly from the copyright holder. To viewa copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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