Immunization in Low- and Middle-Income Countries

Human Resources

The role of trained health workers in the strengthening of health systems is well recognized. The relationship between healthcare worker density and immunization coverage has been well documented in studies from several low- and lower middle income countries ; one of these studies in Turkey also found that the relationship between healthcare worker density and immunization coverage is stronger in rural provinces. Despite the recognition of the problem, there has been little progress in addressing the human resource crisis. However, it is recognized that the solutions are not straightforward and considerable investments in time, effort, and money are required to train and retain health workers. In a 2016 WHO report, the skilled health-worker-to-population ratio in low income (1.3) and lower middle income (3.7) countries was below the threshold of 4.45 per 1,000 population, which is considered to be necessary for meeting the health-related Sustainable Development Goals. The ratios were similarly low in Africa (2.2) and South-East Asia (3.3), which also have the greatest burdens of preventable disease. This implies that lower-income countries, will face difficulties in improving coverage without increases in the number of skilled health workers.

As immunization programs in low- and lower middle-income countries increase in complexity as a result of adding new vaccines and the need to extend coverage to reach 90% or more of their target populations, both the number of health workers and their skill levels will need to be addressed. Specialized skills are required for managing the different components of the vaccine program, such as supply chains, information, and regulatory systems. WHO’s Standard Competencies Framework for the Immunization Workforce aims to provide guidance for countries to strengthen human resource capacity to manage and implement their programs. But national programs still demand more from their health workers without necessarily providing the commensurate training or resources. While training materials and tools exist, program reviews and evaluations reveal gaps in health worker knowledge and practice. Supportive supervision has been shown to improve program performance, but there is still a lack of recognition of the need for and the knowledge and tools to implement supportive supervision in many low- and lower middle-income countries. As is the case with health systems in general, human resource development for immunization remains an underinvested area. Failure to address this critical bottleneck is likely to be a barrier to achieving national goals in low- and lower middle-income countries and global goals.

Sustainable Supply of Vaccines at Affordable Prices

Another key challenge is to ensure a reliable, sufficient, and affordable global vaccine supply. Ensuring an adequate supply of safe and effective vaccines for low- and lower middle-income countries, as well as to each vaccination session in these countries, continues to be a global priority in a world that is seeing unprecedented changes in the vaccine industry and market. In the 1980s, the vaccine market was in serious decline, with many companies exiting the market, viewing vaccines as high-volume, low-margin products. The exit of vaccine producers led to shortages in key products and reliance on a small pool of source suppliers for key vaccine products.

Beginning in 2000 and intensifying since 2005, the vaccine industry has experienced a major turnaround, driven in part by sales of pneumococcal conjugate and human papillomavirus vaccines in high-income countries and the prospects for growth due to Gavi funding in lower- and middle-income country markets. This has been further amplified by the global demand for COVID-19 vaccines. Low- and lower middle income country manufacturers fulfill an increasing role in vaccine supply, and their entrance into the market has stimulated price declines of key vaccines. More than 60% of traditional EPI vaccines are supplied by low- and lower middle income country manufacturers. The Serum Institute of India in Pune, India, supplies more than 80% of measles vaccine to low- and lower middle-income countries. Low- and lower middle-income country manufacturers are increasingly entering into joint development agreements with high-income country vaccine manufacturers to produce new vaccines, and many now participate in a developing country vaccine manufacturers’ network (DCVMN). However, the COVID-19 pandemic has revealed that large inequities in vaccine manufacturing still persist, requiring longer-term investments and commitments to overcome.

The WHO continues to focus on strengthening national regulatory authorities (NRAs) in vaccine-producing countries as weak NRAs have been consistently identified as a major barrier to entry for new suppliers. Multiple criteria in seven basic functions have been developed to determine whether each NRA is able to guarantee that a vaccine is of “assured quality” (national regulatory system; market authorization and licensing; NRA lot release; laboratory access; postmarketing surveillance, including adverse events following immunization [AEFIs] surveillance; regular inspections; and authorization/approval of clinical trials). In June 2018, 43 countries were documented to be producing vaccines for human use, of which 37 had a functional NRA. Twenty-two of these countries were producing one or more vaccines prequalified by WHO for procurement by United Nations agencies, the Russian Federation being the latest addition to the list of countries producing prequalified vaccines.

To sustain the national, regional, and even global supply of EPI vaccines, the most important areas of technology transfer for low- and lower middle-income countries are those relevant to achieving and maintaining good manufacturing practices standards in vaccine production, establishing independent and credible national quality-control laboratories, and instituting national (or regional) regulatory capability. Facilitating successful and sustainable technology transfers is a challenge facing the international organizations that support the global EPI.

Affordability of the newer vaccines, especially for middle-income countries that are not eligible for or will soon lose Gavi support, is becoming an increasing concern. Available information suggests that there is a wide variation in the prices paid by middle-income countries for the same products. However, the solutions are not simple and issues beyond just access to affordable prices need to be considered to support the introduction of new vaccines in middle-income countries not eligible for Gavi support. These issues include strengthened decision-making processes, increased political and financial commitment from national governments, and enhanced public demand for vaccines. These issues have been considered in other sections of the chapter. This section specifically deals with the issues to be considered to secure a sustained supply of vaccines at optimal prices, including the following: (1) efficient procurement processes, (2) efficient regulatory and product registration processes, (3) access to price and contract information, (4) access to revolving funds, and (5) pooled procurement and access to external procurement services.

Previous studies have identified inefficient procurement as a barrier to obtaining competitive prices for vaccines. The support provided to countries in improving their procurement practices has been patchy and remains an area where more needs to be done to secure access to affordable prices.

Inefficient and lengthy processes for the registration of vaccines can drive up the cost for suppliers and consequently the price of vaccines. The barrier that the onerous and lengthy processes pose are likely to have a greater effect on lower cost manufacturers who may not have in-country representatives and fewer resources, thus limiting the choice of products for the countries concerned and resulting in higher prices from a lack of competition. At least 30 middle-income countries not eligible for Gavi support could benefit from more streamlined and efficient regulatory processes.

Available data suggests that increasing price transparency can result in more favorable outcomes from contract negotiations and better prices. While international agencies such as UNICEF and PAHO have started publishing the prices of vaccine procured by them, data on prices paid by self-procuring countries is sparse. The WHO has established the Vaccine Product, Price and Procurement (V3P) web-based platform on Market Information for Access (MI4A) with a goal of increasing vaccine price transparency to inform contract negotiations and decisions on vaccine procurement.

Lack of assurance that suppliers will be paid on time adds to their risk and hence to higher prices. Many middle-income countries face uncertainties about allocation and release of funds for procurement. Others may have legal restrictions about prepayment for goods or face barriers related to currency fluctuation. Revolving funds, such as the PAHO revolving fund, provide solutions to some, but not all, of these problems by providing a line of credit for countries not able to produce the funds at the time when they are needed. However, the existing funds are available only to a limited number of countries in the region. Expanding the access of other middle-income countries to revolving funds may contribute to their being able to access lower prices.

The use of external procurement services, such as through UNICEF, could benefit a number of middle-income countries, especially those with small populations and limited bargaining power. When coupled with a revolving fund, such pooled procurement through external agencies has been shown to lead to lower prices. However, many countries have legal barriers to using external procurement services.

Immunization Supply Chains

The success of essential immunization services in developing countries over the past decades can, to a large extent, be attributed to its backbone—the immunization supply chains that strive to ensure the uninterrupted availability of vaccines at service delivery facilities. These supply chains support the storage and distribution of vaccines in a cold chain to safeguard their potency from the moment they arrive in a country until vaccination. Vaccines are biological products that are sensitive to both heat and freezing, which requires them to be stored within strict temperature ranges in a cold chain system. Their potency cannot be restored if they have been exposed to excessive temperatures.

Historically, the first drive to build cold chain infrastructure in low- and lower middle-income countries following smallpox eradication was during the 1980s under UNICEF’s Universal Childhood Immunization campaign for child survival. With additional impetus from the GPEI during the 1990s, important investments were made to strengthen cold chain systems, primarily to protect vaccines from heat damage. During these two decades, most of the basic six antigens used in national immunization programs had standardized multidose presentations, and vaccine management rules were much simpler, especially with the introduction of the vaccine vial monitor (VVM) in 1996. The VVM is a temperature indicator that measures the cumulative exposure to damaging heat. As well as helping healthcare workers identify if vaccine potency had been compromised by heat exposure, the VVM was also instrumental in the implementation of the open vial or multidose vial policy to reduce vaccine wastage and minimize cold chain capacity requirements.

With the launch of Gavi, the Vaccine Alliance in 2000, the initial goal was to accelerate the introduction of newer vaccines. By then, most of the poorest countries had built up adequate cold chain infrastructure. The 2000s therefore marked a period of relatively flat investment in immunization supply chains, which were not an obstacle to the Gavi goals of increasing routine immunization coverage and ensuring access to hepatitis B and Haemophilus influenzae type b (Hib) vaccines. This reflected the fact that the focus at the time was on new combination products with DTP. The five-in-one pentavalent vaccine made relatively limited demands on cold chain storage and did not require any additional injections.

Gavi in the 2000s did however, support the widespread use of newer and safer technologies for injection in support of the WHO-UNICEF-UNFPA Joint Statement promoting the worldwide switch to single-use auto-disabled (AD) syringes and safety boxes for vaccination. ^, Prior to this, low- and lower middle-income countries were using disposable syringes, an improved technology from the steam-sterilized injection supplies of the 1980s and much of the 1990s, but they were plagued by the high-risk of reuse or needlestick injury causing potential disease transmission (e.g., hepatitis B, hepatitis C, HIV), contamination or serious and sometimes deadly AEFIs. The success story to get all low- and lower middle-income countries to switch to AD-syringes for vaccinations was overshadowed by the unintended consequence of safety and waste management issues it created.

By 2010, however, it was becoming apparent that vaccine supply chain systems had deteriorated during the previous decade and were often operating outside national health systems supply chains. When low- and lower middle-income countries began introducing pneumococcal, rotavirus, and human papillomavirus (HPV) vaccines, these products had significant supply chain implications: the volume of vaccines to store and transport grew by a factor of four, immunization programs needed to manage six times as many doses of vaccines, and there were growing concerns about safeguarding freeze-sensitive vaccines given that the cost of products in the cold chain had increased fivefold. They suddenly became a key bottleneck affecting global immunization goals relating to new vaccine introductions and strengthening of essential immunization services. Many new vaccines came in liquid formulations that were sensitive to freezing, but there was no equivalent of a VVM to indicate if a vaccine had been exposed to damaging freezing temperatures. With at least 35% of vaccines being exposed to extended periods of freezing in low- and lower middle-income countries, safeguarding the potency of newer, more expensive vaccines would require measures for much stricter temperature control.

In 2014, the WHO Immunization in Practice Advisory Committee (IPAC) issued a call to action Immunization Supply Chain and Logistics: A neglected but essential system for national immunization programs. This highlighted that, with few exceptions, immunization supply chains in low- and lower middle-income countries were facing chronic difficulties in ensuring the uninterrupted availability of potent vaccines at service delivery centers, and many government-managed systems were inefficient in vaccine storage, distribution, and stock control. Furthermore, supply chains had failed to adjust to the new requirements of national immunization programmes. They were configured for a different era in immunization and designed to manage fewer, less expensive, and less bulky vaccines and related supplies, where inefficiencies could be tolerated. Considering the billions of dollars that Gavi and other donors were investing in newer and more expensive vaccines, this was no longer the case. Building on the innovative immunization supply chain solutions that emerged from a WHO and PATH collaboration—Project Optimize—the IPAC call to action catalyzed fundamental changes to the design, equipping, staffing and management of supply chains, and how data and funding flow through the system. ^,

In response, WHO and UNICEF rolled out the Effective Vaccine Management (EVM) initiative, supporting an end-to-end, in-depth diagnosis of the strengths, weaknesses and bottlenecks of in-country supply chains, and the development of comprehensive plans for continuous improvements and innovation. Between 2010 and 2014, 70 low- and lower middle-income countries conducted a baseline EVM assessment reviewing nine critical dimensions: cold chain storage adequacy; efficiency in temperature control; compliance with vaccine management policies; vaccine distribution and handling best practices; information systems for forecasting, stock management, and stock control; and adequate infrastructure and maintenance services. The EVM assessment sets a minimum standard for each of these dimensions, based on WHO immunization supply chain norms and guidance.

A 2014 analysis revealed that none of the 70 countries assessed had reached the minimum EVM standards from the national level down to the service delivery and vaccination points. Furthermore, an in-depth review of a sample of health facilities in 57 countries revealed that 20% of those needing to store vaccines were not equipped with any active cold chain equipment; a further 55% had either nonfunctional or poorly functioning equipment, and 23% had functional equipment that was either obsolete or using unreliable technologies. That left only 2% of all cold chain equipment that was functional and with the optimal cold chain technology. Lastly, a 2015 study by WHO estimated that 38% of low- and lower middle-income countries experienced at least one stock-out incident for at least one vaccine for at least 1 month. The extent to which this interrupted vaccination services is not clear, but this evidence pointed to the chronic difficulty of securing an uninterrupted flow of vaccines—a key goal of an effective immunization supply chain system. Within this study, a root-cause analysis conducted between 2010 and 2015 identified poor forecasting, stock management and procurement issues as the cause of 41% of national-level stock-outs and confirmed country weaknesses in basic vaccine management practices.

The combination of neglect and lack of funding has meant that immunization supply chains have failed to evolve and adapt, resulting in delays to the introduction of new vaccines, stock-out of existing vaccines, avoidable wastage, or loss of vaccine potency from storage in weak cold-chain systems. This all had implications in terms of increased costs, lower immunization coverage, and potentially ineffective protection of those vaccinated. These inefficiencies not only undermine the ability to meet immunization targets but also lower the return on health outcomes for those investing in improving immunization programs in low- and lower middle-income countries. ^,

Given this context, in 2016 when Gavi launched its fourth 5-year strategy (2016–2020), it included for the first time a dedicated focus on strengthening immunization supply chains within its health system-strengthening goal. This Gavi strategy and the work of the Alliance partnership is organized around five fundamentals of immunization supply chains.

• 1)

  Supply chain leaders

• While most countries have supply chain managers, few have been professionally trained or educated in supply chain management. Many do not have the authority or resources to improve supply chain performance. The availability of skilled cold chain logisticians has significantly eroded. With more valuable inventories of Gavi vaccines to handle, store and distribute, the pressures have increased to ensure that EVM norms are implemented in countries and that international vaccine management policies are strictly followed. This can only be achieved if there is a dedicated and competent manager, as well as adequate numbers of trained logisticians at all levels of the health system.

• 2)

  Continuous improvement

• Supply chains are dynamic systems that must be continuously monitored, managed, and improved. The WHO–UNICEF EVM initiative builds on international quality management principles to ensure that the skills of supply-chain managers and vaccine logisticians are increased and that a holistic approach to assess, plan and implement change is included within a continuous quality improvement process. ^, The EVM framework for continuous improvements includes leveraging of technological innovations (e.g., in vaccine thermostability), engaging with the private sectors (outsourcing) or strengthening the integration of the vaccine supply chain within the overall national health commodities supply chain. Other opportunities for continuous improvement include identifying ways to determine the optimal dose-per-vial in specific country situations to maximize coverage and minimize vaccine wastage.

• 3)

  Supply chain data for management

• Supply chain managers in countries seldom have information on vaccine stock balances beyond central stores, have incomplete information on cold chain storage capacity, and cannot be sure if vaccine stock-outs are occurring at lower levels of the supply chain. The lack of visibility of vaccine stocks and flows is an obstacle to the timely availability of vaccines and can lead to inefficiencies in the supply chain.

• Many low- and lower middle-income countries continue to manage supply chains with paper-based information systems that do not permit real-time tracking of stock levels throughout the supply chain. With the widespread availability of mobile and cloud-based information and communications technology, networked systems can be established for ordering vaccines, managing stocks and equipment, monitoring consumption and vaccine use, and ensuring that vaccines are kept in the right conditions and are available when and where needed. For instance, in Uttar Pradesh, India, new digital tools were quickly adopted and led to reduced stock-outs and increased vaccine availability after 13 months.

• 4)

  Cold chain equipment

• Significant technological advances have occurred since 2010, including through project Optimize, ^, such as battery-free solar vaccine refrigerators and long-lasting cooling containers for health centers and last-mile usage; the performance, reliability and life-cycle costs of which are significantly better than those of nonelectrical models. These super-insulated containers can store vaccines for more than 30 days using ice and can be retrofitted for Ultra Cold Chain (UCC) applications during health emergencies. During the 2016 Ebola outbreak in West Africa, super-insulated passive cooling containers were the only way that the Ebola vaccine could be kept at –70°C for up to 5 days. This same equipment is being deployed as a UCC solution in response to the COVID-19 pandemic in low- and lower middle-income countries.

• Gavi launched a Cold Chain Equipment Optimization Platform (CCEOP) to deploy equipment that is efficient, sustainable, and better performing to every health facility where it is required at an affordable price. Furthermore, Gavi has a global ambition to shape the market to respond to the demand for affordable and accessible cold chain equipment. This US$250 million 5-year investment in CCEOP represented a US$50 million per year “insurance policy” to safeguard Gavi’s ∼US$1.3 billion per year investment in vaccines for low- and lower middle-income countries. Extending the reach of the cold chain at health center and last-mile levels not only increases availability of vaccines at point of delivery but can also respond to storage capacity constraints up the chain.

• Including the widespread use of electronic continuous temperature-monitoring and freeze-prevention technologies in CCEOP could help reduce incidence of inadvertent freezing of vaccine by 55%. Continuous temperature monitoring has additional advantages of improving the quality of vaccine handling, detecting malfunctioning cold chain equipment, and mitigating damaging temperature fluctuations and freezing even when health workers are not present. ^,

• 5)

  Supply chain systems design

• The supply chain design of most low- and lower middle-income countries has not evolved since the 1980s, when storage points for vaccines and distribution routes mirrored the administrative structure of the health system. While this design proved effective for decades, over time (and often affected by the legacy of multiple health sector reforms), vaccines began to transit through an inordinate number of administrative levels to reach service delivery points. Each stage in this journey posed a risk to the vaccines, from mishandling to breaks in the cold chain. In addition, each point continuously required costly infrastructure expansion.

Recent evidence has highlighted how redesigning supply chain networks can improve vaccine availability, reduce stock-outs, speed up delivery times, increase storage capacity downstream, and reduce costs. One study found that, following the introduction of new vaccines, timely vaccine availability at lower levels of the system could drop by 71% if network design is not adapted, because of bottlenecks in storage capacity. Network redesign has also been shown to reduce the logistics cost of delivering a dose of vaccine to service delivery points by 34 to 60% depending on the network design used. ^, Efforts to optimize supply chain network designs provide countries with more flexible supply chains that can incorporate innovations and provide resilience against emergency situations such as the COVID-19 pandemic.

By 2020, the situation has much improved. Efforts by the partnership to build greater resilience in supply chains are showing results. EVM scores, while not quite meeting the 80% benchmark level, have increased substantially since 2014. There are several countries, like Cameroon, that made significant progress reaching an EVM composite score of 81% compared with 62% in 2013. Another example is the Democratic Republic of the Congo (DRC) that prioritized using 43% of Gavi’s health system strengthening support to strengthen and scale up the five fundamentals of their immunization supply chain. This helped improve the country’s EVM composite score to 70% in 2019, up from 60% in 2014.

For its next 5-year strategy (2021–2025) Gavi will continue its support to strengthening supply systems in low- and lower middle-income countries through the five fundamentals under its equity goal. More broadly, the Immunization Agenda 2030 has placed strengthening immunization supply chains as a key area of focus under its first strategy priority of immunization programs for primary health care (PHC) and universal health coverage (UHC).

Although the situation has improved, without sustained investments and efforts to continuously improve and innovate, there is a risk of reversal which could compromise low- and lower middle-income countries’ ability to achieve IA2030 goals. The level of investments is relatively small. Estimates suggest that investing annually the equivalent of 10% of the annual investment in vaccines would be sufficient to ensure immunization supply chain systems and reach international standards as measured against the EVM standards. Only then, can immunization supply chains hold the promise to facilitate the equitable access and availability of effective vaccines at service delivery points over the next decade, including in emergency situations like the COVID-19 pandemic.

Information Systems: Monitoring and Evaluation of Immunization Programs

A core principle of the IA2030 is to have high-quality, “fit-for-purpose” data to track progress, improve program performance and form the basis of decision-making at all levels. The term high quality when applied to immunization data can be interpreted in many different ways, depending on the intended use of the data. In 2013, the WHO SAGE on immunization highlighted the importance of the need and use of high-quality data both to improve performance and to monitor the results. Data may be considered good quality if it contributes to a complete, unambiguous, meaningful, and correct inference of the status of an immunization system. Data should also be available, analyzed, and interpreted in a timely way, to allow managers to take actions to optimize the performance and impact of the program.

Data required to monitor the performance and impact of immunization programs include the following:

• Data to monitor indicators of program activities and inputs —to detect potential problems with the availability and quality of vaccination services and to identify appropriate solutions;

• Data to monitor indicators of program outputs —coverage of each dose of each vaccine in the national schedule and related indicators of dropout and missed opportunities; these are intermediate indicators that are more easily measured than the measurement of disease impact through surveillance and allow monitoring of progress toward IA2030 and country goals;

• Data on the burden and trends of vaccine-preventable diseases through surveillance (VPDs) —reduced disease incidence and mortality are the ultimate indicators of program success;

• Data on AEFIs —must be monitored to ensure that any such events are detected and investigated, and that an appropriate response is mounted.

WHO and UNICEF collect and compile information annually for all countries on key program indicators through the joint reporting form which has now been launched in electronic format (eJRF). WHO also collects information through reports from various program assessments as well as household surveys. However, beyond reporting to WHO and UNICEF, it is more important that these data and indicators be monitored and used at the district (or other appropriate) administrative level at which the program is managed and nationally. Provision of regular feedback to health workers at all levels of the health system is a powerful way to motivate health workers to improve. In addition to the above groups of indicators, vaccine effectiveness can be monitored through a number of methods described in Chapter 74.