WHAT'S NEW THIS TUESDAY: MEETING OF THE SAGE ON IMMUNIZATION, NOVEMBER 2012

Sunday, 13th of January 2013

Meeting of the Strategic Advisory Group of Experts on immunization, November 2012 – conclusions and recommendations

Text below; also, in French and English, at www.who.int/wer

See http://www.who.int/immunization/sage/meetings/2012/november/en/index.html for the presentations made at the SAGE.

The Strategic Advisory Group of Experts (SAGE) on immunization1 met on 6–8 November

2012 in Geneva, Switzerland. This report provides a summary of the discussions, conclusions and recommendations.2

Report from the WHO Department of Immunization,Vaccines and Biologicals

In 2011, globally 90% of children received the first dose of diphtheria-tetanuspertussis

(DTP) containing vaccine. However, high drop-out rates between the first

dose (DTP1) and the third dose (DTP3) remained problematic in several countries,

resulting in global DTP3 coverage estimated at only 83%. In 64 of the 194

WHO member states, DTP3 coverage was <90%. If every child who received DTP1

also completed the primary vaccination series, an additional 30 countries would

reach the goal of 90% DTP3 coverage. Concerns were expressed over vaccine

coverage, which has remained level over the last few years, and the degree of uncertainty

in global coverage estimates, which is not reported. The degree of uncertainty

both in terms of precision and potential bias is needed to avoid misinterpretation

and a negative impact on policyformulation and implementation.

The African Region (AFR) will celebrate the vaccination of 100 million persons

with a meningococcal A conjugate vaccine.To date, not a single case of meningococ-

cal serogroup A meningitis has been reported in vaccinatedindividuals.

The Region of the Americas (AMR) celebrated the 10th anniversary of the Vaccination Week which has now become a global event. The process to document and verify the absence of endemic measles, rubella and congenital rubella syndrome is progressing well with

the majority of countries and territories having submitted their elimination reports for review by the verification commission. The Emergency Plan of Action to maintain measles/rubella regional elimination in the Americas was developed to maintain high quality surveillance

and high levels of immunization coverage, and ensure effective outbreak response.

The Eastern Mediterranean Region (EMR) has successfully sustained high immunization rates, including in those countries which have recently experienced civil unrest due to high levels of population demand; however there is concern that reductions in coverage may

occur over the longer term if insecurity is prolonged.

The Regional Committee reaffirmed the importance of pooled vaccine procurement for non-GAVI eligible low middle-income countries (LMICs). This initiative will now help these countries to procure pneumococcal conjugate (PCV), rotavirus and Haemophilus influenza

type b (Hib) vaccines through the UNICEF procurement systems.

The European Region (EUR) reported that failure to close the gaps in measles immunization coverage (mostly in older age groups) has led to the recent Europeanoutbreaks.

The South-East Asia Region (SEAR) reported that most countries carried out activities related to the Regional Committee initiative that declared 2012 as the year for

Intensification of Routine Immunization, focusing on increasing access to hard-to-reach, underserved, marginalized and migrant populations.

The Western Pacific Region (WPR) reported serosurveys confirming that nearly all 30 countries have achieved a reduction in the prevalence of HBs antigen carrier rate

from 8% to <2% in children aged <5 years. A new milestone – HBs antigen seroprevalence of less than 1% by 2017 – is now proposed by the Regional Technical Advisory Group on immunization, for review and endorsement by the Regional Committee in 2013.

SAGE acknowledged the global successes in the control of vaccine-preventable diseases but noted that determined efforts were still needed to sustain and enhance these achievements. SAGE stressed that country ownership of immunization as an integral component of primary

care is essential as well as the need to assure corresponding political commitment to this approach from the highest levels of government.

A constraint experienced across Regions was that of repetitive shortfalls in vaccine supply, both for existing vaccination programmes (in particular for DTP-containing vaccines) as well as for new/emerging vaccines, and the impact on vaccine coverage in several countries.

The need for SAGE to address this issue was noted.

At country level, key issues to sustain and enhance vaccination coverage include the strengthening of routine immunization by strengthening management activities and revitalization of basic processes such as interagency coordinating committees and national immunization technical advisory groups.

SAGE expressed strong concern that despite high coverage with primary and booster pertussis vaccination, there has been a recent resurgence of pertussis in some industrialized countries including among the very young. Reasons for this are complex but may include

more rapid waning of immunity with acellular pertussis (aP) vaccines compared to whole cell vaccine. It was agreed that SAGE would establish a working group on pertussis to prepare for a SAGE review of the data and to consider updating current pertussis vaccine recommendations.

As it will take a year to formulate this advice SAGE advised countries considering a switch from whole cell to aP vaccines to await further SAGE guidance, or to themselves carefully review the latest evidence on aP pertussis vaccine effectiveness and the possibility that such a switch may lead to a less favourable outcome in terms of pertussis disease control.

Countries having already switched to aP vaccines are advised to continue vaccinating and await further guidance before making any further modifications to their

programme.

Further to the November 2011 SAGE recommendation, a technical expert group was established to provide advice to WHO on the evaluation of tuberculosis vaccines. This

group will provide guidance on the data that is needed from clinical trials to enable an assessment of the possible public health impact of new tuberculosis vaccines.

The group will also guide interpretation of data from Phase II, III and IV trials, with a particular focus on the assessment of long-term safety and effectiveness.

The SAGE working group on vaccine hesitancy has produced a definition of confidence, developed a matrix of vaccine confidence drivers, and proposed hesitancyrelated

indicators for the Global Vaccine Action Plan (GVAP). Other activities under development include a review paper on the causes of hesitancy and the confidence gap, a systematic review on strategies to improve confidence and their impact, including best practices

and unpublished success stories from countries, and aset of indicators to measure vaccine confidence.

Report from the GAVI Alliance

In June 2012, the GAVI Board approved a revised new vaccine introduction grant to help countries better prepare for the introduction of new vaccines, with increased support for infant vaccines, operational support for campaigns, and support for human papilloma virus

(HPV) vaccine introductions. The Board also approved new windows of support for measles elimination, building on the original US$ 200 million GAVI investments in measles through the Measles Initiative and support for introduction of measles second-dose routine immunization. Additionally, support was approved for the use of measles-rubella vaccine through wide-age campaigns, and controlling and preventing measles and rubella outbreaks

in 6 high-risk countries.

Looking ahead, the Board priorities will include: the approval of the 2013–2014 business plan of the Alliance; reviewing the next vaccine investment strategy; exploring support for inactivated polio vaccine (IPV) pending SAGE guidance; and adopting tailored approaches to

supporting fragile states. On market shaping, new tenders are in process including the first tender for HPV and joint work with UNICEF on options to use market shaping for non-GAVI eligible LMICs. The December 2012 GAVI partners forum and 2013 data summit were

highlighted.

Report from the Global Advisory Committee onVaccine Safety (GACVS)

SAGE was presented with a report of the June 2012 GACVS meeting.3 SAGE acknowledged the detailed review of thiomersal conducted over the years and the accumulated evidence that strongly supports the safety of its use as a preservative for inactivated vaccines. With respect

to the safety of vaccines during pregnancy, SAGE welcomed the early conclusions from GACVS following the review of available evidence on live rubella and trivalent inactivated influenza vaccines. The review confirmed the absence of identified risk to the mother or fetus from the use of these vaccines, and the additional health benefits that result from their use. SAGE highlighted the urgent need for a safety review of other important vaccines that could be used during pregnancy. The new causality assessment scheme recommended by GACVS

for adverse events following immunization was also received with great interest and SAGE requested that this system be pilot tested and reported upon in the future.

Expert Committee on Biological Standardization (ECBS)

SAGE was presented with the outcome of the October 2012 ECBS meeting. This included the adoption of revised recommendations for oral poliovirus vaccines; diphtheria, tetanus, and combined vaccines with DTP antigens; live attenuated Japanese encephalitis vaccines;

and a new guideline for candidate malaria vaccines. ECBS will also initiate the establishment ofglobal standards for vaccines against enterovirus 71, which are being developed in one part of the world with potential for broad public health use.

SAGE had previously requested that a paper be developed, highlighting the circumstances in which off-label use of any vaccine could be recommended, while clarifying the differences between regulatory decisions and public health recommendations. Further to this request,

ECBS was asked to prepare guidance for national regulatory authorities (NRAs) on studies needed to support evidence-based off-label use of vaccines which benefit public health. It was noted that for regulators, product specific data are paramount. SAGE requested that an

additional document be prepared to advise the national immunization technical advisory committees (NITAGs) about the type of data that might support a policy recommendation

to use a vaccine outside its licensed schedule in order to achieve public health benefits such

as operational simplicity or cost savings. SAGE also noted that there is also a need for a communication paper to explain the different perspectives of NRAs and NITAGs at country level.

Immunization Practices Advisory Committee(IPAC)

SAGE was presented with the conclusions and recommendations of the April4 and October5 2012 IPAC meetings.

SAGE considered that the finalization of field guidance for the use of a controlled temperature chain for meningococcal A conjugate vaccine (MenAfrivac®) in a campaign

setting was an important milestone, providing great potential for reaching target populations. SAGE noted IPAC’s programmatic considerations of alternatives to thiomersal-containing vaccines and reinforcement of the key messages on thiomersal, and commended IPAC for

having pursued further review of the programmatic implications of administering IPV as an intradermal dose. SAGE expressed support for the ongoing work to promote the use of solar refrigeration systems for vaccine storage, and encouraged IPAC to pursue other innovative technologies

and strategies that improve vaccine management and delivery, such as cell-phone technology.

Immunization and Vaccine Related Implementation Research Advisory Committee (IVIR)

The IVIR chair summarized the outcome of the September 2012 IVIR meeting. SAGE endorsed the recommendation from IVIR that “while value of statistical life (VSL) may

provide valuable information, there are technical challenges to the measures. Therefore, VSL should not be used as the primary basis for priority setting for vaccines”.

Polio eradication

SAGE commended the countries and the Global Polio Eradication Initiative (GPEI) on the overall encouraging progress towards interrupting wild poliovirus transmission, but noted the increased number of poliomyelitis cases in some districts in Nigeria and Pakistan in 2012

compared to 2011. SAGE commended the level of detailed attention given to polio campaign planning and implementation with clear indications that best practices are being systematically applied. There is an impressive increase in the use and strengthening of

accountability frameworks, training and optimization of polio worker skills, and a visibly improved engagement of leaders and decision-makers at all administrative levels.

SAGE welcomed the long-term vision of the draft GPEI Polio Eradication and Endgame Plan, 2013–2018, and commended the GPEI for the extensive consultative process

used to develop the plan. SAGE endorsed the 4 major components of the plan: (i) interruption of remaining wild type 1 and 3 polio transmission, (ii) withdrawal of the type 2-component of oral polio vaccine (OPV2) use, (iii) containment and certification, and (iv) legacy planning and associated strategic approaches. SAGE supported the priority given to vaccine-associated polio disease (vaccine-associated paralytic poliomyelitis and circulating vaccine-derived poliovirus).

SAGE recommended that the draft Polio Eradication and Endgame plan be revised to include recommendations from current stakeholder consultations. The plan should be reviewed, completed and shared with other partners one month prior to the meeting of the WHO Executive Board in January 2013. The updated plan should provide more explanation for the rationale and public health benefit of the introduction of IPV, the global approach to

switching from trivalent OPV (tOPV) to bivalent OPV (bOPV), and the current efforts and future plans to use ongoing polio activities to strengthen routine immunization systems. The plan should be expanded to highlight, for all major objectives, the importance of using appropriate social mobilization and communication strategies.

SAGE was deeply appreciative of the diligent work of the SAGE polio working group and impressed by the progress achieved by the group in refining the evidence base for introducing IPV to mitigate risks associated with OPV2 withdrawal when replacing tOPV with bOPV for routine immunization (“OPV2 cessation”). SAGE concurred with the main recommendations of the working group.

SAGE recommended that all countries should introduce at least 1 dose of IPV in their routine immunization programme to mitigate the risks associated with the withdrawal of OPV2. SAGE accepted the detailed scientific evidence presented to illustrate the risk-mitigating benefits of IPV use in the context of OPV2 withdrawal, specifically the

evidence to show that, following OPV2 withdrawal, IPV vaccination will help to (i) prevent poliomyelitis in IPVvaccinated individuals exposed to vaccine-derived poliovirus type-2 (VDPV2) or wild poliovirus type-2 (WPV2), (ii) improve the response to monovalent OPV type-1 (mOPV1) or an additional dose of IPV in a type 2 polio outbreak, (iii) reduce the transmission of a reintroduced type 2 poliovirus, and (iv) accelerate wild poliovirus eradication by boosting immunity to wild poliovirus types 1 and 3.

In the context of interrupting wild poliovirus transmission before the end of 2014, SAGE will review progress every 6 months on achieving the prerequisites for OPV2 withdrawal, including the availability of affordable IPV products to ensure the earliest possible date for OPV2 withdrawal but with sufficient advance notification to ensure programmatic readiness and vaccine availability.

SAGE recommended that an IPV supply and funding strategy be established for timely introduction of IPV using existing whole dose products for a transition period

if needed. For its next meeting SAGE requested (i) additional details on the scientific evidence for, and programmatic implications of, targeting expanded age groups during polio campaigns in endemic areas, (ii) a report on the vision for the legacy planning, and

(iii) noting the circulation of VDPV in Somalia andChad, a report of progress in these countries.

SAGE expressed grave concern that because of funding shortfalls, OPV campaigns have been cancelled or scaled back in over 25 high-risk countries in 2012, which poses a threat to the success of the overall programme. This perennial problem exerts considerable pressure on the

programme at a time when eradication is in sight.

Decade of Vaccines Global Vaccine Action Plan(GVAP)6

The session included an overview of progress in putting the GVAP into operation since the 65th World Health Assembly (WHA) in May 2012. Discussions have begun at the Regional level to update regional immunization plans in alignment with GVAP and to establish processes to monitor and report progress to the respective Regional Committees each year. The WHO and UNICEF guidance for preparation of national multi-year and annual plans for

immunization are being updated to align them with the guiding principles and strategic objectives of GVAP and to foster greater alignment with national health sector plans.

The proposed structure and process for monitoring the implementation of the GVAP through a Monitoring & Evaluation /Accountability Framework was described. The framework has 3 elements: (i) monitoring results (based on the indicators for the GVAP Goals and Strategic

Objectives); (ii) monitoring commitments and resources; and (iii) an independent review of progress.

Progress was described in the efforts to finalize monitoring indicators, establish operational definitions, sources of data, and the reporting process. SAGE was presented with the changes made to the indicators since its April 2012 meeting and the rationale for doing so,

and was specifically asked for comments and recommendations.

SAGE discussions mainly focused on: (1) the feasibility and need for surveys to validate district level vaccine coverage measures; (2) adding an indicator of DTP3 coverage ≥80% for ≥3 years; (3) proposed indicators to measure “confidence in immunization”; (4) retention of indicator on district level DTP3 coverage; (5) choice of drop-out rate between the first

dose of DTP and first dose of measles containing vaccine (MCV1) (DTP1-MCV1), or between the first and third dose of DTP vaccine (DTP1-DTP3); (6) addition of a surveillance indicator; (7) addition of an indicator to measure integration of immunization within health

systems; and (8) addition of a vaccine price indicator.

SAGE was presented with plans for mechanisms to document and track commitments to GVAP and resources invested in immunization by national governments and their development partners for low and middle income countries. In addition, the plans to up date the costing, financing and impact work included in the GVAP, specifically addressing areas SAGE had previously outlined, were reported. SAGE provided feedback on the proposed activities for the technical group to take into consideration as they begin their work.

SAGE was pleased to see the work being proposed, including the economic analysis, and the plan to ensure external validation.

Finally, a summary of the process to review and report progress on the implementation of GVAP at the national, regional and global levels was presented. This included the constitution of a SAGE working group that will undertake a detailed review of progress and prepare a report to SAGE on an annual basis. The report, incorporating feedback from SAGE, will form the basis of the WHO secretariat annual reports to the Executive Board and the WHA. The reports to the WHA will also be shared with the independent Expert Review Group for the United Nations Secretary General’s Global Strategy for Women’s and Children’s Health. An open call for nominations of experts to serve on the working group will be initiated.

Members will serve in their personal capacities and will be chosen by a selection panel including representation from the lead agencies for the implementation of GVAP and a representative of the Civil Society Organizations.

SAGE made the following recommendations on the proposed Monitoring & Evaluation/Accountability Framework:

Monitoring indicators

SAGE made specific comments and recommendations on the following:

Goal 3: Meet vaccination coverage targets in every region, country and community.

SAGE noted that district level coverage data are important for monitoring equity in delivery of immunization within countries and for operational and planning purposes.

However, SAGE recognized the important resource requirement for conducting surveys to generate coverage estimates for all districts in a country and proposed that as an alternative, countries may choose to conduct such surveys in selected “high risk” districts that are likely to have low coverage. Such surveys should be done at least twice in the decade.

Strategic objective 2: Individuals and communities understand the value of vaccines and demand immunization both as a right and a responsibility.

SAGE accepted the 2 proposed indicators – % of countries that have assessed (or measured) the level of confidence in vaccination at subnational level with implementation of activities to improve it; and % of un- and under-vaccinated persons in whom lack of confidence

was a factor that influenced their decision – but asked that the last part of the indicator which reads “…with implementation of corrective actions” be deleted. SAGE recommended that these indicators be piloted in AMR and EUR and that the results of the pilots should be reviewed before final acceptance for global use.

Strategic objective 3: The benefits of immunization are equitably extended to all people.

SAGE - recommended that it would be relevant to repeat the indicator on percentage of districts with ≥80% coverage under Goal 3 and Strategic objective 3;

accepted the recommendation that coverage by wealth quintiles be collected for all countries and that in addition, countries also collect and report coverage data by other appropriate equity indicators;
recommended that the SAGE working group consider the possibility of an indicator that would measure equity across as well as within countries

Strategic objective 4: Strong immunization systems are an integral part of a well-functioning health system

SAGE - agreed that an indicator to show sustained high immunization coverage be added, but recommended that the indicator should measure sustained DTP3 coverage of ≥90% for 3 or more years, rather than ≥80%, inorder to ensure consistency with other coverage targets;

accepted the proposal to use DTP1–DTP3 drop-out rate instead of DTP1–MCV1 as the indicator for this strategic objective;
accepted the proposal to add a surveillance indicator, but recommended that the definition of surveillance be expanded to include other vaccine preventable

diseases;

accepted in principle the need for an indicator that would measure integration of immunization systems into broader health systems and coordination between immunization and other primary health care programmes. Such an indicator may be developed for presentation to the SAGE DoV GVAP working group in 2013.

Strategic objective 5: Immunization programmes have sustainable access to predictable funding, quality supply and innovative technologies.

SAGE reviewed the request for inclusion of an indicator on vaccine price but recognized the difficulties involved in developing an indicator that would track prices in all low and middle-income countries. SAGE recommended that an annual narrative report should be prepared on

vaccine price trends for low and middle-income countries, including self-procuring countries, as well as progress on supporting vaccine procurement mechanisms.

Other proposed changes were accepted with the proviso that the SAGE working group should continuously review the need for reformulation of the indicators or mechanisms for collection and reporting of data.

Monitoring commitments and resources and updating the cost and impact analysis for the Decade of Vaccines

SAGE recognized the importance for updating the cost and impact estimates and for setting benchmarks. However, SAGE also recognized the complexity of the analysis and suggested that IVIR and other expert groups and individuals who have experience with such analysis

be consulted on an ongoing basis. SAGE also recognized the urgency for having approximate estimates and recommended that the technical group provide preliminary

estimates for SAGE review in November 2013.

Optimization of Haemophilus influenzae type b (Hib) conjugate vaccine schedules

Hib conjugate vaccines have been in use for >20 years with remarkable success. By 2011, 179 (92%) of countries worldwide had introduced Hib-containing vaccines.

However, WHO estimates that only 43% of infants worldwide received at least 3 doses of Hib containing vaccine in 2011, given the large populations of children in some countries not yet using Hib vaccine and the lack of full implementation or coverage in others with routine use.

SAGE was requested to consider the optimal Hib immunization schedules for children in different epidemiologicalsettings. SAGE discussion was informed by: (i) 3 systematic reviews (2 independent RCTs reviews, 1 on case-control and cohort studies) of the effect of

Hib-containing vaccines on the immune response and on various disease outcomes, (ii) a global review of the epidemiology of Hib disease in children, (iii) a systematic review of Hib vaccine herd effects and, (iv) a review of the long term impact of Hib vaccine in 34 countries

which had introduced the vaccine more than 5 years ago. The outcomes of these reviews were used to define the parameters for a model incorporating the potential of various immunization schedules and of improvements in vaccine delivery timeliness and coverage, in order to assess impact on disease burden.

During the discussion, SAGE members noted that the evidence on the number of primary doses and the need for booster doses requires further evaluation before recommendations can be made on optimizing the current schedule. In particular, the experience of the

United Kingdom, where the introduction of Hib vaccine into the childhood immunization programme in 1992 led to an initial reduction in the incidence of Hib disease

in all age groups followed by a subsequent resurgence, needs to be further evaluated. There were a number reasons that may have contributed to the Hib resurgence: these include waning immunity after a 2/3/4 month priming schedule possibly exacerbated by the use of combination vaccines containing aP, together with the lack of boosting due to the herd immunity effect of the UK programme on Hib carriage (achieved as a result of high coverage and a catch-up programme to 4 years of age). This illustrated the complexity of the issues surrounding recommendations as to the optimal schedule for use of Hib vaccines in different epidemiological settings.

SAGE considered that the information regarding the interval between doses should also be re-analysed and that additional immunological studies should be considered.

A more in-depth evaluation of duration of protection after each dose of Hib containing vaccine was also necessary. SAGE also recommended additional review view of evidence on the potential effect of Hib combination vaccines including those that include aP.

The outcomes of the above reviews should also be used to refine the model assumptions and parameters. A refined version should be submitted once more for appraisal by Hib experts to ensure that the revised assumptions and parameters have made it more realistic. SAGE recommended that a revised summary of the evidence, including a critical appraisal of the evidence with GRADE tables and justification for proposed recommendations, should be presented to SAGE in April 2013.

Measles and rubella

SAGE commended countries and Regions for the remarkable progress made in reducing measles mortality globally during the last 3 decades, contributing significantly to the 4th Millennium Development Goal. This progress would not have been possible without country commitment and the support of many partners.AMR has achieved elimination of both measles and rubella and the WPR is approaching interruption of endemic measles transmission. In addition, the number of countries using rubella vaccine in their

routine childhood immunization programme has been steadily increasing. However, despite this progress, a careful assessment of the comprehensive reports presented indicates that based on current trends and programme performance, the 2015 global targets as well as Regional elimination targets in EUR (2015), EMR (2015) and AFR (2020) will not be achieved on time. SAGE urged countries and partners to raise the visibility of measles and rubella elimination activities and to ensure that they receive adequate priority and resources as a central component of the GVAP.

In keeping with the GVAP target of measles and rubella elimination in at least 5 WHO Regions by 2020, SAGE urged SEAR to establish a measles elimination goal and

AFR, EMR, SEAR and WPR to work towards establishing regional rubella elimination goals.

SAGE endorsed the Global Measles and Rubella Strategic Plan for 2012–2020 and recommended full implementation of the key strategies in a manner that promotes

country ownership, strengthens the immunization system, promotes equity and reinforces linkages with polio eradication and other programmes. SAGE noted that some key components of the strategic plan remain under-funded and urged countries and partners to work towards closing this funding gap.

In 2011, >20 million children did not receive their first dose of measles vaccine on time and countries with low routine immunization coverage continue to experience the highest burden of measles. SAGE noted the innovative use of measles supplementary immunization

activities to improve routine immunization service delivery and recommended that countries and partners should plan and implement specific strategies to strengthen routine immunization systems as part of measles and rubella control and elimination activities.

Despite increases in MCV1 coverage and the introduction of MCV2 as part of routine immunization programmes, large outbreaks have occurred in a number of countries in Europe, Africa and Asia over the past 24 months. SAGE noted the changing epidemiology of

measles, with a shift in age distribution of cases towards older age groups, which is consistent with a programme that primarily targets young children. SAGE urged countries to conduct in-depth investigations of their outbreaks to determine the underlying reasons and the role of these older age groups in sustaining transmission, and to develop approaches to target these older age groups as appropriate. In considering age groups for measles vaccination, rubella

susceptibility in older age groups also needs to be addressed.

SAGE noted the gaps in the immunization coverage and surveillance data needed to guide the programme. Regions and countries are urged to strengthen reporting of district-level vaccination coverage, strengthen an integrated measles and rubella case-based, laboratory supported surveillance of fever and rash illness, and introduce surveillance of congenital rubella syndrome.

Closer linkages between measles and rubella programme activities and the GPEI has well-recognized benefits. As GPEI elaborates its legacy planning as a component of its endgame strategic plan, SAGE recommended that countries and global immunization partners

assess the potential synergies and take active steps, where appropriate, to adapt and apply the polio infrastructure and lessons learnt to support achievement of measles and rubella elimination targets and strengthening of routine immunization programmes.

SAGE welcomed recent GAVI investments in measles and rubella control which provide significant additional resources for increasing routine coverage, measles-rubella and measles supplementary immunization activities, and timely outbreak response vaccination.

SAGE recommends that countries seize this unique opportunity and commit additional national resources to ensure that programme planning and implementation is of the highest quality. Each campaign should follow established “best practices” and be independently

evaluated to ensure homogeneous vaccination coverage of >95%.

SAGE endorsed the working group’s plan that includes: refining immunization strategies to address the changing epidemiology of measles and rubella; strategies to strengthen surveillance and monitoring, including the definition of an appropriate indicator of district-level coverage; and development of a prioritized list of research topics.

SAGE reviewed and endorsed the draft framework for verification of measles and rubella elimination and encourages regions and countries, as they approach elimination, to adopt this approach. The framework should be evaluated and adjusted over time, based on country experience.

SAGE was concerned by the challenges and high costs resulting from the continuous importation of measles into countries which have achieved elimination, and suggested that the possibility that international travel regulations could potentially reduce the likelihood of

measles importation be explored.

SAGE welcomed the report from the measles aerosol project. This project, led by WHO, aims to achieve licensing of at least one method for respiratory delivery of a currently licensed measles vaccine. SAGE was presented with data from clinical studies, especially on a Phase II/III trial in India. The results from the pivotal non-inferiority immunogenicity trial showed that the per-protocol seropositivity in the aerosol arm was 85.4% (95% CI: 82.5%, 87.9%) as compared to 94.6% (95% CI: 92.7%, 96.1%) in the subcutaneous arm, with

the difference in seropositivity being -9.2% (95% CI: -12.2%, -6.3%). This difference and the upper limit of the confidence interval were both greater than the non-inferiority margin of 5% defined in the study protocol. SAGE members concluded that the tested aerosol vaccine may not be suitable for primary vaccination of infants against measles.

Nevertheless, SAGE recognized the potential benefits of a measles aerosol vaccine because it could be used by non-health-care workers in low-resource settings in the context of outbreaks, acute emergencies and outreach. It advised that the development of a combined measles rubella aerosol vaccine should be pursued, including demonstration studies of field acceptability and potential to contribute to increasing coverage in resourcelimited

settings, expansion of safety data, additional studies to adjust the dose delivered, and cost-effectiveness. SAGE also noted the potential usefulness of the aerosol route for administration of other vaccines.

Vaccination in humanitarian emergencies

In April 2012, SAGE was presented with a draft framework on the use of vaccination during humanitarian emergencies. Although the framework could not be pilot tested during real emergencies, as requested by SAGE in April, a field exercise was carried out in the

Horn of Africa. The draft framework was applied to a situation in South Sudan to decide on the appropriate use of PCV and Hib vaccines among displaced populations. Active feedback was solicited and received from key stakeholders. A proposed final draft of the framework

incorporating all feedback received was presented to SAGE for approval. It was noted that this framework should not override other guidelines for specific vaccine-preventable diseases (VPDs), though in most cases (e.g. measles) the framework is compatible and complementary.

The framework comprises 3 steps which should be applied iteratively as the humanitarian emergency evolves: (i) an assessment of the epidemiological risk posed by each VPD; (ii) for those VPDs with a high-risk burden, consideration of the vaccine properties and a context specific analysis of logistics for a mass campaign; and (iii) for vaccines judged to be suitable for intervention, prioritization in relation to other urgent public health actions and in light of contextual factors such as political realities, security issues, as well as available

human and financial resources.

The revised framework is provided for expert analysts at the coordination/policy level rather than front line health-care workers. It is intended to guide decisionmaking processes to ensure the most effective use of vaccines in emergency settings. SAGE proposed that the current approach covering only acute emergencies could be extended to more chronic emergency situations where normal services have not resumed after the acute emergency is over and there may be opportunities for other vaccine interventions, such as to nonimmunized

populations, or where polio eradication is a priority.

SAGE endorsed the revised framework as a major step forward and considers that it fills an existing gap but acknowledged that the framework focuses on vaccination which is only one priority consideration in humanitarian emergencies. SAGE strongly affirmed the potential utility of this framework and recommended pilot testing in the field. The working group was asked to adapt the document and proceed with further pilot tests before finalization.

Administrative and financial issues often present difficulties for vaccination delivery in humanitarian emergencies. Procurement, as specified in the document, is limited to prequalified vaccines and it was suggested that the use of vaccines in humanitarian emergencies should not be restricted to such prequalified vaccines. This should be further reflected in the framework to assist with procurement and development of fast-track

registration processes for donated vaccines and the potential off-label use of vaccines. SAGE noted that a cross reference to other WHO guidelines for emergencies including the use of other interventions, and for the use of vaccine donations, would be useful. High level messages about other priority interventions should be emphasized.

SAGE noted that the list of VPDs to be considered as part of the framework should be extended to include rabies, and that the current categorization of vaccines should be changed to focus on the mode of transmission of the pathogen. SAGE also requested that the

document give consideration to herd immunity, and that the list of risk factors of the epidemiological risk assessment as noted in step (i) be extended to consider chronic diseases as a general risk factor for VPDs. The key ethical consideration of non-maleficence should be

clarified as referring to risk-benefit in these settings. SAGE noted that ethical issues were embedded in the framework, but agreed that an extended explanation of ethical principles and ethical guidance for informed consent should be included.

Consideration was given to the potential inclusion of case studies in the documents but this was debated, as disasters are very diverse. It was left to the workinggroup to decide whether these should be included.

New vaccine introduction in middle-income countries (MICs): current initiatives to address financial challenges

In 2008 7 and 2010 8 the SAGE made a number of recommendations to WHO regarding assessing and addressing the challenges faced by middle-income countries (MICs)

in immunization, particularly in the introduction of new vaccines.

SAGE was presented with a draft paper entitled “Global Support for New Vaccine Implementation in Middle-Income Countries”. The information provided in the

paper was complemented by presentations from WHO, the former Yugoslav Republic of Macedonia, and UNICEF.

SAGE noted that the MICs have a combined population of 5 billion and an annual birth cohort of 96 million and are home to nearly 75% of the world’s poorest populations. Providing support to MICs for immunization programmes and new vaccine introduction is critically important for equity, both between and within countries.

Since 2000, 40 of the 111 MICs have received support from the GAVI Alliance, 3 countries have graduated from support, and a further 16 will graduate in 2015–2016. SAGE noted that significant health gains have been made by those countries eligible for GAVI support, gains

not apparent in countries which have not had access to either GAVI funding or to technical assistance from partners. Those MICs graduating from GAVI support will require assistance from development partners in the transition from that support. SAGE noted that some of the MICs are struggling to introduce new vaccines, in part due to an inability to access pricing appropriate to the country’s economic status. As an example, a dose of HPV vaccine was reported to cost 4 times less in one Western industrialized European country than in one Eastern European developing country.

SAGE noted that the constraints for non-GAVI eligible MICs to introduce new vaccines extend beyond pricing and procurement, and include equity, sustainability, regulation, capacity building and partner support. The focus of development partners on a restricted group of countries and subsequent concentration of technical support and capacity building in these areas has limited the support available for other countries. MICs in the EUR also report a lack of capacity to address negative attitudes towards new vaccines among parents and

medical workers.

Specific projects such as the Vaccine Product Price and Procurement Project (V3P), EMR pooled vaccine procurement efforts, activities within the Pan American Health Organization (PAHO) revolving fund, and the UNICEF MIC strategy (including pooling demand from MICs and defining ceiling prices) are ongoing or under development. SAGE acknowledged their importanceand potential as they represent bold steps in moving forward.

In complement to the efforts made by AMRO/PAHO and UNICEF on vaccine price transparency, SAGE considered that the V3P project would allow for improved

availability of reliable information on vaccine products, prices and procurement to be used for countries’ decision-making. To optimize the outcomes from these projects, SAGE noted the need for significant country capacity building.

SAGE appreciated the efforts made by WHO, UNICEF and GAVI and other partners to extend discussions about vaccine supply and pricing to MICs where appropriate, and the adaptation of some activities to suit MIC-specific needs. However, SAGE noted with concern

that these efforts are fragmented and are failing to optimize synergies in the work being undertaken by each agency.

The proposed coordination policy and strategy outlined in the GVAP paper included options for how to optimize outcomes by seeking an enabling environment through capacity building, technical assistance, and system strengthening, as opposed to direct financial assistance

or charity. SAGE noted that if partners worked together it would be possible to build on existing efforts and capacities, and use the comparative advantage of each partner to create new synergies. SAGE recommended, as a priority, the creation of a task force convened by

WHO as a mechanism for inclusive stakeholder engagement and forum for harmonization and implementation of projects and activities.

SAGE recommended continued efforts towards improving the transparency of vaccine pricing. Actions should also include ensuring that manufacturing capacity is

sufficient to meet the increasing needs of MICs.

SAGE noted that with a modest investment technical assistance and capacity building could be significantly strengthened.

SAGE noted that the lack of access to life-saving vaccines in MICs has not significantly improved since this was first raised in 2008 and that rapid action is now required. SAGE requested that this issue and achievements be revisited in a subsequent meeting.

Footnotes

1 See http://www.who.int/immunization/sage/en/index.html

2 The complete set of presentations and background materials used for the SAGE meeting of 6–8 November 2012 together with summarized declarations of interests provided by SAGE

members are available at http://www.who.int/immunization/sage/meetings/2012/november/en/index.html; accessed in

November 2012.