We developed search terms to identify articles that included information describing the impact of new vaccine introduction on immunization systems and health systems [2] (Table 1). The terms were selected to be inclusive and were developed with input from immunization experts. The search terms were divided into two broad categories: (1) vaccines and (2) immunization and health systems, and databases were searched to identify articles captured by at least one search term in each category (Table 1).

We searched seven publication databases (Medline^®, Embase^TM, Nursing Update, West African Journal of Nursing, CINAHL^®, Web of Science^®, and Global Health) that are relevant to vaccines and immunization programs, and are likely to contain reports from low income countries. We attempted to use identical terms to search each database; however, as each database had certain specifications, it was sometimes necessary to modify some terms. We limited the search to reports involving human subjects, published in any language. The final search date was September 29, 2010 and was not limited to a beginning year.

We reviewed the title and abstract of each article identified using the search strategy to determine whether the article was potentially relevant (i.e., contained quantitative or qualitative information on the impact of new vaccine introduction on the immunization system, the broader health system, or both). Potentially relevant articles were referred for a full abstraction. Articles that discussed disease incidence, disease burden, vaccination coverage, serotype replacement, immunization campaigns, or adverse events following immunization were included if they contained data or discussion of vaccine impact on the health or immunization system and assessed outcome within the first five years after vaccine introduction, unless the assessed outcome manifested more than five years after vaccine introduction (e.g., HepB vaccine and hepatocellular carcinoma or cirrhosis, or HPV vaccine and cervical cancer). Cost effectiveness studies were considered if they included real-time data, and real situations and savings and were not based on results of modeling. Expert opinion articles were included if data were reported. We excluded clinical trials, because they did not show impact on the immunization and health systems following vaccine introduction.

We used EndNote X3.0.1S (Thompson Reuters) to organize and track the articles, adding databases sequentially beginning with Medline, and performing automated and manual de-duplication following the addition of each subsequent database. Each article was reviewed to determine if it addressed the impact of the vaccine introduction on the immunization and health system. Sixteen immunization experts from the World Health Organization (WHO), the Centers for Disease Control and Prevention (CDC), The United Nations Children’s Fund (UNICEF), the London School of Hygiene and Tropical Medicine and Hygiene (LSHTM), the Program for Appropriate Technology in Health (PATH), and Maternal and Child Health Integrated Program (MCHIP) participated in the abstraction process. Information from relevant articles was abstracted using a Microsoft Access^® 2007 data collection form and were organized according to the WHO Framework for Action (Fig. 1); this framework was created by WHO in 2007 to promote a common understanding of health care systems by providing a systematic means for considering the essential functions [2]. The Framework comprises six building blocks: service delivery; health workforce; information; medical products, vaccines and technologies; financing; and leadership and governance. Countries were grouped by gross national income into categories according to the World Bank Atlas Method [http://data.worldbank.org/about/country-classifications/country-and-lending-groups]. Non-English articles were reviewed and abstracted by native speakers, whenever possible. A random sample of 10% of the articles were reviewed and abstracted by a second reviewer. If discordance was found, the article was reviewed by the first author to resolve discrepancies.

The search yielded 24,768 articles from December 31, 1911 to September 29, 2010, among which 8973 (36%) were found to be duplicates (Fig. 2). Reviewers applied the inclusion criteria to the remaining 15,795 titles and abstracts. Among these, 654 (4%) articles met the inclusion criteria and were referred for full abstraction; 49 (7%) of these were in languages other than English. One hundred twenty-nine (20%) of the 654 abstracted articles were found to be relevant for the analysis. In addition, one key article known to the authors that was not identified by the systematic search of the published literature was included, resulting in a total of 130.

Among the 130 studies included in this review (Table 2), 97 (75%) were from high income countries; 21 (16%) were from middle income countries; and 4 (3%) were from low income countries. The studies included vaccines targeting 10 diseases (hepatitis A (3 [2%]), hepatitis B (24 [19%]), Hib disease (28 [22%]), HPV infection (13 [10%]), influenza (1 [1%]), Japanese encephalitis (1 [1%]), meningococcal meningitis (17 [13%]), Streptococcus pneumoniae disease (28 [22%]), rotavirus diarrhea (14 [11%]) and typhoid (2 [2%])). Multiple vaccine formulations (i.e., antigens, adjuvants, stabilizers, preservatives and other components) and vaccine combinations were represented in the studies. Overall, 64 (56%) studies considered vaccine introductions that took place between 2000 and 2008.

In a number of countries, introduction of the new vaccines required new delivery strategies or modification of existing delivery strategies. While many new vaccines have been introduced through routine vaccination programs and mass campaigns, other delivery strategies, including one-time catch up vaccination, school-based vaccination, or a combination of strategies, depending on the vaccine and age recommendation for vaccination have been utilized to introduce new vaccines [3-10]. Novel delivery strategies, and the need for social promotion and education about the new vaccine’s safety and potential adverse events, may also affect the delivery of other immunization and health services. In several high and middle income countries coverage with existing vaccines administered through routine childhood or school-based strategies increased (Australia, Germany and Peru) or remained the same (Thailand and the United States) when new vaccines were introduced [11-16]. In Canada, offering PCV at no cost helped to remove existing inequities in PCV distribution [17], increased PCV acceptance and improved on-time vaccination [17,18]. Australia’s government-funded HPV vaccination strategy consisted of school-based routine vaccination of 12-year-old girls, including a 2-year catch-up strategy [5]. The catch-up strategy for 13–18 year olds was largely school-based, and for 18–26-year-old women was carried out by general practitioners. The general practitioner visit was also intended to provide an opportunity for physicians to broaden sexual health education and discuss cervical cancer prevention [5]. However, ensuring completion of the series for those who missed school-based vaccination required additional efforts, including coordination with general practitioners, additional mop-up campaigns at the end of the year, or establishing an individual recall system.

Communication and education activities were often coupled with delivery of new vaccines. Social mobilization to publicize vaccination – including through mothers’ clubs and professional organizations – was part of successful efforts to ensure wide acceptance of HepB vaccine in Singapore [19], China [20], Taiwan [21] and Peru [15], and of Hib vaccine in Uruguay, Chile, Qatar, and Kuwait [22]. Introduction of HPV vaccine in the UK involved engagement of multiple stakeholders and was facilitated through the establishment of an HPV vaccine implementation group [23]. Knowledge and education about the disease and the vaccine, including safety issues, aided the successful introduction of Hib [24] vaccine and HepB vaccine [25] vaccine in Canada and Hib in the United Kingdom [26]. In the United States and Canada, HPV vaccine, in contrast to other routinely recommended childhood immunizations, was actively marketed through direct consumer advertising and public awareness campaigns that targeted legislators and policy makers in addition to consumers [27]. In the United Kingdom, funding for media communication about meningococcal conjugate C vaccine was included in the budget for vaccine introduction [28]. Because adding a new immunization can result in an additional injection during a routine childhood vaccination visit, immunization planners in Israel chose a Hib vaccine with a 2-dose rather than a 3-dose series, in part to avoid three injections at the 6 month visit [29]. In Australia, some vaccine providers were reported to be reluctant to administer three injections at one time, resulting in lower uptake of PCV in a high-risk population [30].

There was variability in the impact of new vaccine introduction on the health workforce. In settings where vaccination was introduced into regularly scheduled clinics, little impact on staffing and appointment times was observed, as was the case with Hib vaccine introduction in Sweden [31], HPV vaccine introduction in Australia [32], and PCV introduction in the United States [11]. Vaccine introduction into adolescent and adult immunization programs sometimes required additional staff or adjustment of appointment times: in Scotland, adding pneumococcal vaccine to appointments for influenza vaccination among older adults increased consultation times by about 2 min [33]. Additional staff were needed for HPV vaccine introduction in the United Kingdom [34], where public health nurses, pediatric nurses, health visitors, and managers were recruited into teams, and additional funding was made available to address a shortage of school nurse vaccinators. Lack of staff was reported as a barrier to HPV vaccine introduction in remote areas of Australia [5], and HepB vaccine introduction in juvenile justice facilities in the United States [35].

Training of health staff at national, regional and local levels was required for successful HepB vaccine introduction in China [36] and Zimbabwe [37], hepatitis A and Japanese encephalitis (JE) vaccine in China [38], Hib vaccine in the Americas [39,40], and meningococcal polysaccharide vaccine in Egypt [3]. When the new vaccine was introduced as a combination product that included a vaccine already used in the childhood vaccination schedule [22], training was relatively straightforward. In Zimbabwe the introduction of HepB vaccine also included development of communication materials, and training on community mobilization activities [37]. In Indonesia, training, and periodic re-training in the local language were needed to successfully implement the school-based typhoid program [10]. Continuing education was conducted in Italy to promote the birth dose of HepB vaccine [41]. To ensure funding for training, the vaccine introduction budget for HepB and Hib vaccines in Ethiopia included a training and education component [42].

In other countries, vaccine introduction stimulated the development of new surveillance or vaccine registry systems, including comprehensive surveillance for meningococcal meningitis in the United Kingdom [4], pediatric invasive pneumococcal disease in Canada [43], hepatitis B virus-associated nephropathy in South Africa [44], and an HPV immunization registry in Australia [16,45]. In Chile and Uruguay, Hib case definitions and disease reporting forms were standardized, and a technology transfer program was developed following Hib vaccine introduction [39]. A national immunization register, implemented at the same time as a meningococcal conjugate B vaccination campaign in New Zealand, was used to monitor coverage, safety and effectiveness assessments [46]. In Australia’s HPV vaccination program, a time-limited incentive payment of $6 per notification of vaccination was offered to general practitioners to improve completeness of the vaccine register [45]. In China [47,48], Malawi [49], South Africa [50], Nicaragua [51], Canada [52] and Egypt [3], existing disease surveillance systems were used for impact evaluation, policy formulation, and program advocacy related to immunization against HepB [48], JE [47], Hib [49,50], rotavirus diarrhea [51], pneumococcal pneumonia [52] and meningococcal meningitis [3,3].

The availability and use of new technologies, including combination vaccines and auto-disable (AD) syringes, had an impact on the immunization system. In Chile (DTP-Hib) [53], the United States (DTP-Hib) [54] and Zimbabwe (DTP-HepB) [37], use of combination vaccines resulted in fewer injections, and the need for fewer needles and syringes; lower administrative costs; and reduced storage capacity, compared with introducing a new vaccine as a separate vaccine injection. Introduction of DTP-Hib vaccine in The Gambia; however, resulted in initial interruption of routine DTP immunization due to irregular supply of the combination vaccine [55].

In some instances, introduction of new vaccines created additional requirements for cold chain and logistics systems. In Ethiopia, the replacement of 10-dose vials of whole cell diphtheria–tetanus–pertussis (DTwP) vaccine with single-dose vials of pentavalent (DTwP–Hep B–Hib) increased transport and cold chain requirements [42]. The need for additional cold chain capacity was also reported for rotavirus in several Latin American countries [56], hepatitis A and B vaccine introduction in China[20,38], HPV vaccine introduction in the United States [35], and 23-valent pneumococcal polysaccharide vaccine (PPV23) for older adults in Scotland [33]. In other cases, as was the case for Hib introduction, existing infrastructure was adequate for introduction [39].

As part of new vaccine introduction, AD syringes, safety boxes, and injection safety policies were introduced into immunization programs. In an evaluation of 58 countries eligible for funding from the GAVI Alliance that received injection safety support, all but two continued exclusive use of AD syringes and safety boxes after funding ended [57,58]. In some countries, the use of AD syringes, safety boxes, and injection safety policies were expanded beyond the immunization program to other health services. Most countries were able to continue the use of AD syringes after GAVI funding for injection safety support ended.

Cost was a consideration in planning new vaccine introduction, including introduction in developed countries [57]. Utilizing existing infrastructure or combination vaccines reduced the costs for introduction, as was documented with introduction of DTP-Hib in the US [54], combination HepA/HepB vaccines in Spain [58], and Hib vaccine in Sweden [31]. In a number of settings, insufficient funding [22] and loss of donor support [37] resulted in vaccine shortages and program interruptions.

A decrease in ambulatory consultations and hospitalizations, disease-related complications, and long-term sequelae associated with diseases prevented by the newly introduced vaccines was reported from developing and industrialized countries; these led to reductions in health care utilization, and in some cases resulted in changes in treatment recommendations [31,44,55,59-89] (Table 3). The introduction of PCV in the United States resulted in a decrease in the mortality in sickle cell patients; however, guidelines for penicillin prophylaxis remained unchanged, because not all pneumococcal serotypes are covered by currently available vaccines [90]. In Brazil, all-cause diarrhea costs declined following introduction of RV vaccine, but they were not sufficient to offset the costs of program implementation [82]. Targeted strategies to vaccinate high-risk populations reduced or eliminated racial and ethnic disparities in rates of Hib disease incidence in Israel [91] and Australia[92,93] and of pneumococcal disease in the US [94] were decreased or eliminated following vaccine introduction. Populations not targeted by the vaccine experienced reductions in morbidity and mortality associated with Hib disease [24,39,91,95-100], Streptococcus pneumoniae disease [43,83,101-107], meningococcal disease [3,9,108-114], hepatitis A [58], hepatitis B [115], typhoid fever [6], rotavirus diarrhea [116-123], human papilloma virus infection [124,125], and Japanese encephalitis [47]; these reductions were attributed to a herd protective effect.

The introduction of new vaccines has created interest in the development of diversified and innovative funding sources and mechanisms for vaccine introduction and sustainability. For example, innovative mechanisms such as bridge funding from the Vaccine Fund [49]; World Bank, UNICEF, USAID and WHO [42]; and the GAVI alliance [126] have accelerated and increased the coverage of new vaccines in low income countries. However, lack of financial planning impacted program sustainability in some countries [49,127].

New vaccine introduction impacted various aspects of the vaccine recommendation and regulatory processes. In Australia, Belgium, Canada, Chile, Greece, Taiwan, United Kingdom, United States, and Uruguay [4,21,27,39,128,129], existing national regulatory institutions and advisory committees were used to license and develop recommendations for new vaccines. Frequently, subcommittees were formed to develop recommendations for the specific vaccine, often in collaboration with academic pediatric and infectious disease organizations [39] and disease-specific societies[21,129].

Planning of vaccination campaigns has gone beyond the immunization program to include the departments of education, health, and defense; academic institutions and local government [10,21]. In some countries, legislation was enacted to promote vaccine implementation or evaluation. For example, Italy had a law requiring routine infant HepB vaccination and catch-up vaccination of unvaccinated adolescents [130], and failure to comply had the potential to result in the temporary suspension of paternal authority to ensure immunization of the minor [131]. In Australia, legislation enabled the establishment of a national registry to collect data to assess HPV vaccination coverage [45].