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Contents lists available at ScienceDirect

Vaccine

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yphoid vaccine introduction: An evidence-based pilotmplementation project in Nepal and Pakistan

. Imran Khana,∗, Alfred Pach 3rda, Ghulam Mustafa Khanb, Deepak Bajracharyad,ushant Sahastrabuddhea, Waqaas Bhuttab, Rehman Tahirb, Sajid Soofie,handra B. Thapad, Nilesh Joshi c, Mahesh K. Puria, Parisha Shresthad, Shyam Raj Upreti f,

ohn D. Clemensa, Zulfiqar Bhuttae, R. Leon Ochiaia

International Vaccine Institute, Seoul, Republic of KoreaTrust for Vaccines & Immunization, Karachi, PakistanMITRA Samaj, Kathmandu, NepalGroup for Technical Assistance, Sanepa, NepalAga Khan University, Karachi, PakistanMinistry of Health and Population, Government of Nepal, Nepal

r t i c l e i n f o

rticle history:vailable online xxx

eywords:yphoidsianteric feverakistanepal

a b s t r a c t

The World Health Organization (WHO) in 2008 recommended the use of currently licensed typhoid vac-cines using a high risk or targeted approach. The epidemiology of disease and the vaccine characteristicsmake school-based vaccination most feasible in reducing typhoid disease burden in many settings. Toassess feasibility of school-based typhoid vaccination, two districts in Kathmandu, Nepal and two townsin Karachi, Pakistan were selected for pilot program. Vaccination campaigns were conducted throughthe departments of health and in partnerships with not-for-profit organizations. In total 257,015 dosesof Vi polysaccharide vaccine were given to students in grades 1–10 of participating schools. The vac-cination coverage ranged from 39 percent (38,389/99,503) in Gulshan town in Karachi, to 81 percent

i polysaccharides vaccineaccination campaign

(62,615/77,341) in Bhaktapur in Kathmandu valley. No serious adverse event was reported post vaccina-tion. The coverage increased for vaccination of the second district in Pakistan as well as in Nepal. Therewas an initial concern of vaccine safety. However, as the campaign progressed, parents were more com-fortable with vaccinating their children in schools. Supported and conducted by departments of healthin Pakistan and Nepal, a school-based typhoid vaccination was found to be safe and feasible.

© 2015 Published by Elsevier Ltd.

. Background

Typhoid fever has been in existence since antiquity, with foundn ancient Chinese text dating back to 100 AD [1]. Although thisisease has been controlled in much of the industrialized world, itontinues to affect people in many developing countries [2]. Basedn previous global disease burden estimates, typhoid fever has theighest incidence in South Asia and Southeast Asia which consti-ute 90% of estimated global enteric fever cases (includes Salmonella

Please cite this article in press as: Khan MI, et al. Typhoid vaccine inNepal and Pakistan. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccin

yphi and Salmonella Paratyphi A, B and C infections). However,ecent estimates for Africa have reported incidences comparableo those in Asia, with reported outbreaks more common in Africa

∗ Corresponding author. Present address: 2000 Pennsylvania Ave NW, Suite 7100,ashington DC 20006, USA. Tel.: +1 202 621 1698; fax: +1 202 842 7689.

E-mail address: khan.m.imran@outlook.com (M.I. Khan).

ttp://dx.doi.org/10.1016/j.vaccine.2015.03.087264-410X/© 2015 Published by Elsevier Ltd.

than in Asia [3]. Children and adolescents are the most affectedage-groups in high endemic countries [4–6].

Typhoid fever is caused by the bacterium Salmonella entericaserotype Typhi (S. Typhi) and is spread by the fecal-oral routethrough contaminated food or water [7,8]. Typhoid fever is char-acterized by persistent, high-grade fever and abdominal pain;illness often lasts one month or more [9]. In about 10–15% ofcases without appropriate antimicrobial therapy, it leads to seri-ous complications, including hypotensive shock, perforation of thegut, and gastrointestinal hemorrhage [7]. Rapidly increasing ratesof antibiotic resistance have increased the difficulty and cost oftreatment and are threatening to increase case fatality from thecurrently estimated rates of 1–4% to the pre-antibiotic era rates of

troduction: An evidence-based pilot implementation project ine.2015.03.087

10–20%[10].Preventive measures include improved water and sanitation

systems, but given the huge investment required, they are distantgoals for most typhoid-endemic countries. In 2000 and 2007, the

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orld Health Organization (WHO) recommended typhoid vaccina-ion as a control strategy [11]. In its 2009 meeting, the WHO Southast Asia Regional Office (SEARO) recommended prioritizationf typhoid vaccines for “immediate” implementation.1 However,yphoid vaccines have not yet been regularly used in typhoid-ndemic regions.

Safe and effective typhoid vaccines have been available sincehe early 1990s [12]. But public-sector use has been limited andhey have never been used in a large scale vaccination program.n response to this, the International Vaccine Institute’s Vi-basedaccines for Asia (VIVA) Initiative accelerated the adoption of the

yphoid Vi-polysaccharide vaccine in high risk areas. To deter-ine program feasibility and population acceptance of typhoid

accination, pilot typhoid vaccination programs were carried outn two districts in Kathmandu, Nepal and two towns of Karachi,akistan.2 Nepal and Pakistan were selected based on their highisease burden, their previous use of typhoid vaccines, and theirovernments’ willingness to take the lead in the conduct of theaccination campaigns. A school-based vaccination campaign wasesigned for this project, as governments in the Southeast Asiaegion have demonstrated that school-based programs are an effec-ive approach for achieving high coverage [13–15]. Furthermore,ince approximately 70% of cases occur in children less than 15ears of age in high risk regions [16], vaccinating students will likelye critical for the reduction of typhoid fever disease burden.

. Methods

.1. Planning phase

.1.1. Designing the pilot vaccination programKey stakeholders needed to implement the pilot typhoid vac-

ination program were identified. In both countries, the keytakeholders included government public health officials (Depart-ent of Child Health, Ministry of Health and Population in Nepal;

nd the Expanded Program on Immunization, Ministry of Health,indh, in Pakistan), pediatricians, academics, and, in the case ofepal, the Program for Immunization Preventable Diseases Officef WHO. A series of discussions with these stakeholders were heldo identify: (1) the sites for vaccination; (2) target ages for vacci-ation; (3) the modality of vaccine introduction; and (4) supportrganizations and groups required for vaccine introduction.

Upon discussion with government officials, it was found thatarticipation of the government immunization program was essen-ial for the planning, management, and execution of the pilotaccination program. Their recommendation was to share the tasks.he local governments in Nepal agreed to conduct the vaccination,hereas the Trust for Vaccines and Immunization (TVI) took the

ead in Pakistan with support from the Ministry of Health. Due toxtensive nature of research data collection, public officials sug-ested that other non-governmental agencies could be involvedn planning, managing, recording, and analyzing the results of theilot vaccination program.

Please cite this article in press as: Khan MI, et al. Typhoid vaccine inNepal and Pakistan. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccin

.1.2. Study geographic settingWhen deciding on the pilot vaccination sites, the key stake-

olders suggested considering: the number of doses available;

1 http://www.who.int/immunization/sage/Report SEARO Vaccinerioritization wshop.pdf.2 Vi-based Vaccines for Asia (VIVA) Initiative: The Vi-based Vaccines for Asia

VIVA) Initiative was a 5-year project implemented by the International Vac-ine Institute. The VIVA Initiative aims to reduce the burden of typhoid fever ineveloping countries through the adoption of Vi-polysaccharide vaccines, and theevelopment, testing, and licensure of affordable next-generation Vi-conjugate vac-ines.

PRESSxx (2015) xxx–xxx

previous experiences in piloting national vaccination program(s);existing collaborations between health and education bodies; andpotentially influential districts/towns, so that the success of theprogram could inform other districts/towns. In Nepal, the pilotschool-based vaccination programs were planned in two districtsof the Kathmandu Valley, Lalitpur and Bhaktapur. In Pakistan, theywere planned in two out of 18 towns in Karachi, Gulshan andJamshed.

2.1.3. Study population and eligibility criteriaThe target for the school-based vaccination was children in

grades 1–10 (approximate ages 5–15 years old). The governing bod-ies for public and private schools are different in both countries.These entities were repeatedly visited and informed about thebenefits of vaccination, and subsequently included in the pro-gram. In Pakistan, an important addition was the religious schools,madrasahs, which were in neither the public nor private schoolsystems.

2.1.4. Advocacy and endorsementAppropriate approvals and support for the vaccination program

were sought from relevant local authorities in both countries. Thisprocess was initiated in partnership with key stakeholders. The firststep was to gain the support of local authorities through repeatedadvocacy visits, and providing scientific information on the dis-ease, preventive methods, available vaccines, and the profile ofthe Vi polysaccharide vaccine. In response to the advocacy visits,local authorities granted the necessary approvals and support tofacilitate social mobilization activities.

2.1.5. Formative research, social mobilization, andcommunication activities

Since typhoid vaccination is not routinely done in thesecountries, and a range of stakeholders (e.g., parents, healthcare providers, community representatives, religious leaders, andschool and health officials) were involved, it was deemed neces-sary to inform and mobilize these groups to increase participationin the school-based typhoid vaccination. Formative research wasconducted among parents, teachers, and local health care providersto assess their perceptions, knowledge, attitudes, and interest intyphoid fever and use of the Vi polysaccharide vaccine against thedisease. We also explored credible and common sources of informa-tion for acquiring additional knowledge about the disease and thevaccine. The study was conducted between June 2009 and March2011 in Nepal and Pakistan.

The project utilized a comprehensive communication strat-egy that took into account the concerns and questions of thetarget groups. IEC materials (brochures, posters, flyers, and ban-ners), radio jingles, television announcements, and a documentarywere developed and pre-tested. Additionally, a series of orienta-tion meetings was carried out with teachers, students, and parentswhen requested by school staff.

2.1.6. Social mobilization monitoringTo assess social mobilization and communication strategy, head

teachers and parents were regularly interviewed during the courseof the field implementation.

2.2. Vaccination campaign

2.2.1. Strategy development and training

troduction: An evidence-based pilot implementation project ine.2015.03.087

Standard operating guidelines were developed for the vacci-nation activities. Vaccinators and other staff were trained on thenature of typhoid fever, the typhoid vaccine, safe injection prac-tices, adverse event following immunization (AEFI) management,

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old chain maintenance, waste disposal, and vaccinationogistics.

.2.2. VaccinationThe Vi polysaccharide vaccines (Typhim Vi®) was donated by

anofi Pasteur, France, in 20 dose vials for Nepal. In PakistanTypbar®) was purchased on a subsidized price from a local man-facturer (AMSON Vaccines and Pharma, Pakistan) and was aono-dose ampoule. Vaccines were given intramuscularly.Because it was the first time the typhoid vaccine was to be

elivered through the schools, a consent form was used to ensurehat parents were adequately informed about the pilot vaccina-ion project. Only students who had completed informed consentorms were allowed to be vaccinated. Students with fever wereonsidered ineligible for receiving the vaccine.

All schools were informed of the visit by the vaccination teams indvance. In case the vaccination coverage was lower than expectednd a school wanted a follow-up visit, the school was revisited byhe vaccination teams.

.2.3. Adverse event following immunization (AEFI) monitoringnd management

Each vaccination team included a medical professional who wasesponsible for observing the students for 15–30 min after vacci-ation for the detection and management of immediate seriousdverse events. Each vaccination site had an AEFI kit, and a hospi-al was identified in case of serious reactions. All of the vaccinationtaff members were trained in AEFI management. Every studenthat was vaccinated was given contact numbers of the physiciansn charge of the campaign, in case of complaints outside of workingours.

A call center was set up at the campaign office that handled ques-ions from parents and school staff regarding typhoid fever, venuend dates for vaccination, eligibility requirements, and informationn vaccine safety.

.2.4. Institutional review board approvalsThe study was approved by the institutional review boards of the

nternational Vaccine Institute, the Nepal Health Research Coun-il, and the Ethical Review Board of Aga Khan University, Karachi,akistan.

. Results

.1. Planning phase

.1.1. Formative researchThe formative research involved qualitative data collection in

ine focus group discussions (FGD) and 10 in-depth interviewsIDIs). Trained teams were organized to collect and analyze the data.his data was used to guide the development of social mobilizationtrategies and IEC materials and messages through consultativeeetings with two nonprofit organizations, MITRA Samaj in Nepal

nd Trust for Vaccines and Immunization (TVI) in Pakistan.The findings of the formative research indicated that: (1) there

s a need to clarify what the symptoms of typhoid fever are; (2)here was awareness of risks for the disease, but also misconcep-ions regarding its causes; (3) many thought there were effectivereventive measures (e.g., safe water, clean food) but they alsohought they were at risk in some situations; (4) all thought theaccine would be beneficial, but they needed confirmation that

Please cite this article in press as: Khan MI, et al. Typhoid vaccine inNepal and Pakistan. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccin

he pilot vaccination was not a clinical trial, and requested morenformation on the vaccine side effects and duration of protection;5) teachers, medical personnel, and local government administra-ors were considered credible sources of information; and (6) radio,

PRESSxx (2015) xxx–xxx 3

television stations and print materials (e.g., posters) were identifiedas common sources of information.

3.1.2. Information communication strategyThe social mobilization teams were trained on typhoid fever, the

project’s aims and objectives, communication skills, and the deliv-ery of social mobilization materials and messages. There was alsoan orientation session for the call center attendants, which involvedrecording incoming queries and providing initial responses.

A comprehensive communication strategy was designed basedon the formative research that included direct approaches as well asindirect approaches. Direct approaches included banners, posters,and one page information sheets were distributed. Radio jinglesand television commercials were broadcasted for one week priorto the start of vaccination. A media sensitization workshop wasorganized for journalists at this time. Three different visits for socialmobilization were made at all of the sites (Table 1).

3.2. Vaccination campaign

3.2.1. Strategy development and trainingBoth Nepal and Pakistan had school-based vaccinations in

the past – measles vaccination in Pakistan, and measles andJapanese encephalitis vaccinations in Nepal. The vaccination strate-gies and training programs were built upon the experiences fromthose vaccination programs. Some elements were modified and/orstrengthened, including social mobilization activities and vaccinesafety monitoring.

Each vaccination team consisted of two vaccinators and a vacci-nation assistant. The teams in Pakistan were led by a physician. InNepal, vaccination teams were led by vaccinators at the vaccinationcenters (schools) with proper supervision by senior project staff.Physicians, however, regularly visited each vaccination site withmedicine and an Adverse Event Following Immunization (AEFI)management kit to observe and respond to any adverse reactions.

3.2.2. VaccinationVaccination in these settings was conducted at different time

points based on the field requirements and modifications inthe implementation strategy. Overall, the vaccination began onOctober 2010 in Gulshan town of Karachi, Pakistan, and ended inLalitpur District in Nepal on January 2012.

Nepal: The vaccination program began in Lalitpur District inAugust 2011 and was completed in January 2012. The munici-pality (LSMC) schools were vaccinated first followed by VillageDevelopment Committees (VDCs) (rural area). Students in theBhaktapur municipalities (Bhaktapur and Thimi) and BhaktapurVillage Development Committees were vaccinated from December2011 through January 2012.

In Lalitpur, there were 122,044 students in the target age group(grades 1–10) in 498 schools. The majority were in private schools(70%). Vaccination coverage ranged between 63% in private schoolsof VDCs and 65% in public schools.

In Bhaktapur, a total of 62,615 students, among 77,341, in 349schools (171 public and 178 private) were vaccinated, with a cover-age rate of 76% in public schools and 85% in private schools (Table 2).

Pakistan: A total of 437 and 941 schools were selected for vacci-nation in Gulshan town and Jamshed town, respectively. In Gulshantown, 38,419 (38.6%) students were vaccinated in total. In Jamshed

troduction: An evidence-based pilot implementation project ine.2015.03.087

town, 78,246 (59.6%) students were vaccinated in total. Most ofthose vaccinated were from private schools. The coverage by thetypes of school ranged between 33% and 68% and was highest inthe madrasahs (Table 3).

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Table 1Social mobilization and communication plan for school based typhloid vaccination in Nepal and Pakistan.

Expec ted Aud ience W1-4 W1-3 W1-2 W1-1 W1 W2 W3 W4 W5 W6 W7 W8 W9 V1 V2 W1 W2 W3Head tea che r 200 - 30 0Mad rasah Admin ~ 70

Tea che rs 30 schoo ls at least

Parents 30 schoo ls at least

Hea lth Care Provide rs ~ 100 0

Announ cemen ts Paren ts/Mosque s 150 ,000 - 200 ,00 0

Exhibition General Population 2 Million

Pamph lets/Brochu res Paren ts 150 ,000 - 200 ,00 0Tea che rs ~ 500 0

Hea lth care provide rs ~ 100 0

Hand Bill s/Flyers Paren ts 150 ,000 - 200 ,00 0

Tea che rs ~ 500 0

PosterHea lth Care Provide rs/Hospitals ~ 100 0

Paren ts/Studen ts 150 ,000 - 200 ,00 0

Banne rs Paren ts 150 ,000 - 200 ,00 0

Cab le TV Gene ral Popu lation 1.2 Milli on

TV Hea lth Sho ws Gene ral Popu lation 1.2 Milli on -

Rad io (Publi c Service message ) Gene ral Popu lation 1.2 Milli on -

News Pape r (typho id related articles) Gene ral Popu lation 1.2 Milli on -

Press Release Gene ral Popu lation 1.2 Milli on - Pre t esting Mon itoring Evalua tionSocial Mobili zation Data Coll ection

Print Med ia

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Semina r

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Weeks since the start of the social Mobili zation

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Table 2Vaccination coverage results from the school based vaccination campaign in Lalitpur and Bhaktapur District, Nepal.

Lalitpur Bhaktapur Total

Educational institutions 498 349 847Public 207 42% 171 49% 378 45%Private 291 58% 178 51% 469 55%

Total number of children 122,044 77,341 199,385Public 36,320 30% 32,025 41% 68,345 34%Private 85,724 70% 45,316 59% 131,040 66%

Total children vaccinated 77,765 64% 62,615 140,380Public 23,662 65% 24,243 76% 47,905 70%Private 54,043 63% 38,372 85% 92,415 71%

Adverse events 155 <1% 68 <1% 223 <1%

Table 3Vaccination coverage results from the school based vaccination campaign in two towns of Karachi, Pakistan.

Gulshan Jamshed Total

No. % No. % No. %

Total target population 99,503 43%a 131,323 57%a 230,826Educational institutions 437 31.7a 941 69%a 1378

Public 59 14% 131 14% 190 14%Private 302 69% 543 58% 845 61%Madrasah 58 13% 257 27% 315 23%Others 18 4% 10 1% 28 2%

Total number of children vaccinated 38,389 39%a 78,246 61%a 116,635Public 6738 18% 18,834 24% 25,572 23Private 25,739 67% 42,458 54% 68,197 57%Madrasah 5299 14% 14,547 19% 19,846 15%

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.2.3. Adverse event following immunization (AEFI)Nepal: In Lalitpur, during the vaccination campaign, a total of

18 (0.3%) AEFI cases was reported in the LSMC schools, and 370.07%) in the VDC schools. In Bhaktapur, 68 (0.1%) AEFI cases wereeported. The most common AEFIs were pain at the injection site,ever, headache, and vomiting. All of these cases were followed upnd confirmed to have been resolved. There were no hospitaliza-ions following any vaccinations.

Pakistan: A total of 205 (0.3%) AEFI cases were reported dur-ng the vaccination campaign (156 cases in Gulshan town and 49ases in Jamshed town). All of the reported AEFI cases were minorvents. All of the cases were followed up and confirmed to haveeen resolved. There were three hospitalizations following vaccina-ion (two had fever after vaccination, and one was misinterpretedy the study staff as a serious adverse event, and hence neededospitalization).

. Discussion

The primary observation from this pilot introduction programas that school-based vaccination programs for the typhoid vac-

ine were safe and acceptable in the four communities of Nepal andakistan. This was achieved through extensive planning and estab-ishing collaborative partnerships. Currently, typhoid vaccines areot used in routine public health immunization programs. The

essons from this pilot program can possibly be translated to futurechool-based programs with other new and non-routine vaccines.

While the level of involvement varied, local government officialshealth and education), private school associations, religious lead-rs (in Pakistan), community leaders, medical associations, regionalain clinics and hospitals, and communication agencies played

mportant roles in the program.

Please cite this article in press as: Khan MI, et al. Typhoid vaccine inNepal and Pakistan. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccin

Typhoid fever is a common disease in these communities, –ased on both epidemiological studies describing the incidencef the disease and people’s perceptions articulated during forma-ive research [17]. While the disease is well-known, the attitudes

2407 3% 3020 58%49 0.003% 205 0.003

and understanding of the benefits of vaccination varied. This wasreflected in the varying coverage rates among different communi-ties where the pilot vaccination program was conducted, despitesimilar planning and execution. However, as the vaccination pro-gram was being implemented, the information reached moreparents and increased overall confidence. Hence during the courseof the vaccination campaigns, vaccination coverage improved(identified as findings from the social mobilization monitoring).This highlights two factors that were found to be significant: (1)a vaccination communication strategy should be flexible in orderto address the concerns of major stakeholders, especially parents,in real time; and (2) once a new vaccine is introduced, the targetpopulation may be initially hesitant, however, after witnessing reg-ular cycles in the use of the vaccine without major adverse effects,it will develop confidence in the program.

Typhoid fever has been successfully controlled in many partsof the world through a combination of sanitation, water supplyimprovements and vaccine use [14,18,19]. Most of these initiativeswere part of government control strategy to control the disease andhas been successful in countries such as Thailand and Chile whichare no longer endemic for typhoid fever. However, a continuousstand-alone typhoid vaccination has not been carried out. Manyhave been parts of the projects to assess efficacy and field effective-ness and with the results influence global and national decision insupporting vaccines financing, however, Gavi, the vaccine alliancethat is the major donor for vaccine financing in developing worldstayed away from supporting the current licensed typhoid vaccinesin 2008 and then reconfirmed their decision in 2013 in support ofconjugate vaccine, which is not yet WHO prequalified. All studieshave shown great promise in the control of disease by vaccina-tion only, however, robust analysis of health impact data has notbeen done with all these vaccination projects that could influence

troduction: An evidence-based pilot implementation project ine.2015.03.087

decision making.The main difference between the settings in Nepal and Pakistan

was the school systems. In Nepal, most schools are public in natureand managed by the government sector, while a large number

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f schools are private and managed by several different entitiesn Pakistan. Overall coverage rates were substantially lower inakistan than in Nepal, but when considering the public schools,he coverage rate was higher in Pakistan. Higher acceptance inhe public sector may be due to immunization activities that aresually carried out in public schools (e.g., measles immunization),specially in Pakistan.

This could also be due to the fact that public schools fall underhe government structure and have to follow the instructions fromhe Ministry or Department of Health. Many private schools inakistan did not allow access to the students despite presentinghem letters from the Ministries of Health and Education. In Nepal,he situation varied and was largely dependent on the acceptancef the administration. Of importance, however, was trust in therogram in all settings. The advocacy strategies were highly influ-ntial on vaccine coverage. Informal post-vaccination evaluationf the program suggested that parents or caretakers who had seenhe information (banner and/or leaflet) or heard the radio jingleere more likely to have received the vaccine regardless of being

n public or private schools (data not shown).Major lessons were learned through the use of the informed

onsent forms given to the parents as a permission slip for theirhild to receive the vaccine. Many parents were hesitant in signinghe consent form and thus resulting in their children missing theaccination (data not shown). The consent form was also usefuls a communication channel between the school administration,accination administration, and parents. There were benefits toequiring an informed consent process, such as ensuring that ade-uate information on the disease and vaccine use was providedo the parents and institutional freedom from liability for schools.owever, the higher vaccination coverage in the second rounds

n Nepal, where a signed consent form was not required, sug-ests that the consent requirement may have affected participation.owever, this has to be analyzed systematically from the post-accination evaluation data.

. Conclusion

The pilot typhoid vaccinations conducted in the schools ofepal and Pakistan were safe and acceptable. They were a goodxample of a public-private partnership, wherein the governmentmplemented a vaccination program in collaboration with a localon-governmental organization; an international organization thatrovided technical assistance and funding; and for-profit vaccineanufacturers.

Please cite this article in press as: Khan MI, et al. Typhoid vaccine inNepal and Pakistan. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccin

onflict of interest statement

All authors declare there is no conflict of interest.

[

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