Closing the Global Immunization Gap: Delivery of Lifesaving Vaccines Through Innovation and Technology

Sachin N. Desai, MD,* Deepak Kamat, MD, PhD† *International Vaccine Institute, Seoul, South Korea †Department of Pediatrics, Wayne State University, and Children’s Hospital of Michigan, Detroit, MI

Objectives After completing the article, readers should be able to:

1. Review challenges of immunizing children in resource limited settings. 2. Discuss current successes and limitations of operational strategies in the development and deployment of vaccines to the areas of greatest need. 3. Introduce innovative approaches and future interventions to address key logistical challenges encountered with vaccine delivery in developing regions.

Abstract

One of every 5 children does not receive basic vaccines because of concerns related to storage and delivery in resource limited countries. Transporting vaccines over long distances in extreme temperatures is a common challenge. Issues that involve production and formulation, delivery technologies, cold chain logistics, and safety factors need to be addressed to properly adapt vaccines to resource constrained settings. Current successful field interventions include United Nation Children’s Fund cold boxes, which are used to store and distribute vaccine in disaster struck areas, and vaccine vial monitors, which allow health workers to gauge whether vaccine is still usable in areas with unreliable electricity AUTHOR DISCLOSURE Drs Desai and Kamat fi and refrigeration. This review aims to provide a general overview of have disclosed no nancial relationships relevant to this article. This commentary does innovative approaches and technologies that positively affect vaccine not contain a discussion of an unapproved/ coverage and save more lives. investigative use of a commercial product/ device.

ABBREVIATIONS STRENGTHENED INFRASTRUCTURE TO GET VACCINES WHERE THEY CDC Centers for Disease Control and Prevention NEED TO BE DTP Diphtheria and tetanus toxoids and pertussis By preventing up to 3 million deaths and protecting more than 100 million lives PATH Program for Appropriate from illness and disability, vaccines are one of the best investments in health. (1) Technology in Health Aggressive efforts against polio have decreased polio burden by 99.8%, and WHO World Health Organization complete eradication would save an estimated US $50 billion by 2035. (2) The VVM Vaccine Vial Monitor

e32 Pediatrics in Review Downloaded from http://pedsinreview.aappublications.org/ by guest on September 23, 2021 Expanded Programme on Immunization has contributed Administration of vaccines in large multidose vials minimized enormously to reduce the burden of debilitating vaccine costs for older vaccines and permitted wastage rates that ex- preventable diseases, such as measles, diphtheria, pertussis, ceeded50%insomecases.(7)Thishighwastageratewas tetanus, and polio. Vaccines have the ability to save and deemed acceptable, and even encouraged, as an alternative to transform lives, allowing children to grow up healthy, attend delaying the opening of a new vial and potentially missing an school, and improve their earning potential. Simply put, opportunity to vaccinate. vaccines create wealth for the world’s poorest regions, where The launching of the Decade of Vaccines collaboration infectious diseases account for almost half of all deaths. (3) and the validation of a new Global Vaccine Action Plan However, 22 million infants are still not fully immunized require a reenergized global effort to ensure increased with routine vaccines. Despite significant accomplishments political support, improved vaccine delivery, strengthened in vaccine coverage, challenges leading to limited access to research and development of new vaccines, better supply vaccination parallel many of the barriers similarly encoun- security, and increased affordability. (8) The Decade of tered in achieving access to health care in many of these Vaccines collaboration represents a straightforward vision settings. These obstacles include political instability, con- for major international multilateral organizations to work fl ict, social and economic isolation, and traditional antivac- together to meet the challenge of achieving universal access cine beliefs . The novel strategies presented in this brief to immunization set forth by the World Health Assembly in review represent examples of modern technologies that May 2012. To adapt vaccines to poor settings, critical topics fi could be useful in helping eliminate one signi cant road- to be discussed are production and formulation, delivery block to immunizing all children. technologies, supply chain logistics, and safety factors. These innovations will play a central role in advancing CURRENT SITUATION AND CHALLENGES the use and deliver of vaccines to hard to reach populations.

Reaching marginalized communities in remote areas, poor urban settings, and politically unstable regions continues to BETTER VACCINE FORMULATIONS be an obstacle in narrowing the immunization gap. Success- Optimizing vaccine production methods will help in achiev- ful distribution in these areas requires the transport of ing stronger and broader immune responses, reducing vaccines in extreme temperatures over long distances adverse events, and improving stability in extreme heat between health centers. Even with improved global and cold (Table 1). Traditional vaccines include components Expanded Programme on Immunization coverage rates, of infectious organisms, which provide stronger immune an estimated 20% of the world’s children 5 years and responses but at the cost of unacceptable adverse effects. younger do not receive the full 3-dose course of the diph- Most newer vaccines consist of highly purified recombinant theria and tetanus toxoids and pertussis vaccine (a common proteins, resulting in lower levels of immunogenicity. Con- proxy for childhood vaccination rates) as a result of high sequently, new methods use highly purified synthetic ad- vaccine prices, weak health care systems, and technical juvants to provide enhanced protection without a difficulties. (4) Unfortunate examples are highlighted in generalized nonspecific immune response (Table 2). Indian states, such as Bihar, where the 3-dose DTP vaccine coverage rates of 40% lag at least 30% behind other states, such as Tamil Nadu and Kerala. Disparities in these vaccine VACCINE SUPPLY CHAIN AND LOGISTICS SYSTEMS coverage rates exist in countries such as Ethiopia, where Vaccine Infrastructure and Thermostability figures by the World Health Organization (WHO) are re- Countries have relied on the same storage and transport ported as high as 86%, whereas the Ethiopia Demographic systems for more than 3 decades. High rates of wastage have and Health Surveys have documented rates as low as 37%. (5)(6) Countries eligible for discounted pricing through the GAVI Alliance (formerly the Global Alliance for Vaccines TABLE 1. and Immunization) have seen the total cost for purchasing Characteristics of an Ideal Vaccine a full course of Expanded Programme on Immunization • Single-dose regimen with prolonged duration of protection vaccines (initially targeting tuberculosis, diphtheria, tetanus, • Simple to transport, store, and administer • pertussis, polio, and measles) increase from US $1.37 per child Safe with no adverse effects • Affordable and inexpensive in 2001 to more than US $38.80 per child in 2011. (4) These • High stability against extreme heat and cold figures do not factor in programmatic or wastage-related costs.

Vol. 35 No. 7 JULY 2014 e33 Downloaded from http://pedsinreview.aappublications.org/ by guest on September 23, 2021 distances are required to reach remote populations. Alumi- TABLE 2. Role of Adjuvants in Vaccine num adjuvant–containing vaccines, on the other hand, Development (1) display an increased sensitivity to unintentional freezing, especially when vaccine is placed too close to the walls of ice- • Decrease the dose of vaccine • Decrease the number of doses lined refrigerators or frozen ice packs. The effects of tem- • Shorten onset and prolong duration of response perature damage are vast; suspected damaged vaccines are • Induce mucosal immunity often discarded at great cost to the immunization program, • Enhance immune response in very young and old recipients whereas unnoticed damage results in children receiving potentially ineffective vaccine. Substantial advances in bet- ter passive cooling equipment, such as reengineered cold been tolerated since traditional vaccines could be acquired boxes, are being used to move vaccines in areas that require in large quantities at a very low cost. With international extended travel periods from 6 to 10 days without the risk of vaccine prices reaching $5 to $7 per dose for vaccines against freezing. Both this and the prospect of battery-free solar rotavirus, human papillomavirus, and pneumococci, there refrigerators for use in isolated health centers and clinics are is clearly a new environment in maximizing efficiency. (9) expected to save considerable expenses. The Centers for (10) To minimize unnecessary wastage, new vaccines are Disease Control and Prevention (CDC) offer a comprehen- packed in 1- and 2-dose vials bundled with syringes and sive toolkit on vaccine storage and handling that outline other delivery devices. This results in a marked increase of recommendations on cold chain maintenance and equip- price and amount of cold storage space required (Figure 1). ment, routine storage and handling, inventory manage- The increased volume results in increased shipments and ment, and emergency procedures for protecting workload due to limited space in trucks and cold rooms. In- inventory. (14) Realizing that cost is a major barrier for creasing energy costs certainly compound pressure on the poorer countries to achieve these best practice strategies, the existing system. CDC acknowledges that these are guidelines meant for Natural disasters, such as annual flooding, can cut people interim guidance, encouraging practices that move toward off from the outside world. Such events unfortunately are full implementation of these recommendations. (15) common in many resource limited areas and remind us of Laboratory and field studies have validated the feasibility the need for a controlled temperature system, which is not of using certain vaccines outside the cold chain in ambient reliant on electricity and adaptable to local health systems. temperatures for a limited period immediately preceding Maintaining a 35.6°F to 46.4°F (2°C-8°C) cold chain can dosing when used alongside vaccine vial monitors (Table 3), prove to be extremely difficult in these settings. Heat has the which is often the most logistically difficult and complex potential to damage vaccines in areas where power outages part of the cold chain to maintain. Early discussions with the and fuel shortages can prevent refrigerators from operating, manufacturer and countries with high meningitis disease as well as settings where transportation of vaccine over long burdens were instrumental in the success of achieving

Figure 1. Cumulative value and volume of vaccines used in routine childhood vaccinations in Ethiopia. (10)(11)(12) Reprinted with permission from Program for Appropriate Technology in Health. Building Next Generation Vaccine Supply Systems. December 20, 2013. All rights reserved. Available at: http://www.path.org/publications/detail.php?i¼2175. (13)

e34 Pediatrics in Review Downloaded from http://pedsinreview.aappublications.org/ by guest on September 23, 2021 TABLE 3. Vaccine Vial Monitors: Saving Money, Saving Lives (16)

A vaccine vial monitor (VVM) is a label that contains a heat sensitive material that is placed on a vaccine vial to register cumulative heat exposure over time. The inner square of the VVM is made of heat sensitive material that is light at the starting point and becomes darker with exposure to heat.

After an earthquake in Yogyakarta, Indonesia, much of the health infrastructure and electricity was lost for several days, resulting in nonfunctional refrigerators. Despite the heat, VVMs revealed that most vaccines were not damaged and were able to be used, resulting in the saving of 50,000 doses, which would have been otherwise needlessly discarded.

Since their introduction in 1996, more than 2 billion VVMs have been used. The World Health Organization (WHO) and United Nation Children’s Fund estimate that VVMs will allow health care workers to recognize and replace more than 230 million doses of inactive vaccine and to deliver 1.4 billion more doses in remote settings, saving at least US $5 million each year.

WHO/Umit Kartoglu, Bandung, Indonesia

VVMs allow for use of a controlled temperature chain, which would achieve the following: • Reduce costs and system constraints • Reach more people • Target appropriate groups B (Infants; hepatitis B birth dose; pregnant females: tetanus toxoid; and adolescent girls: human papillomavirus) • Reduce the risk of vaccine freezing

the successful label revision of meningococcal type A vac- are available where they are needed. Regrettably, in many cine in October 2012, stating the following: “In situations countries, half of all vaccine doses are never administered, where maintaining the 2-8°C storage is not possible, both and many more are wasted because of unintentional freez- MenAfrivacTM and its diluents can be stored at temperatures ing, heat exposure, expiry, and other mishaps. (23) Innova- not exceeding 40°C (104°F) for up to 4 days, provided the tive solutions are also required for inefficient management, vaccine vial monitor has not yet reached its endpoint and the paper-based tracking systems, and outdated policies that can expiration date has not been reached.” (17) This controlled disrupt vaccine delivery before they reach the people who temperature chain strategy has been successfully used in need them. Many middle-income countries with sufficient other countries, such as Chad, China, India, Indonesia, electricity, telecommunication, and transportation often Mali, and Papua New Guinea, and during the final legs of are using immunization systems designed before the distribution. The examples of the new meningococcal vac- advent of personal computers, the Internet, or cell phone cine and an experimental rotavirus vaccine in Table 4 serve networks. By efficiently managing information and storing to illustrate how the innovation of partnership can serve to vaccines, countries can enhance immunization logistics overcome 2 of the biggest challenges in delivering vaccine systems. throughout developing regions: the heat and high cost. Implementing web-based tools to track and report vac- cine stock movements and collect data on immunizations Information Systems and Immunization Logistics given could positively affect accuracy and timeliness of For more than 30 years, ministries of health have created vaccine stock records, reporting burden, and ability to track and maintained logistics systems that receive, store, trans- vaccines in case of a recall. Use of a digital immunization port, and refrigerate vaccines with the hopes that vaccines registry system using cell phone technology to help track

Vol. 35 No. 7 JULY 2014 e35 Downloaded from http://pedsinreview.aappublications.org/ by guest on September 23, 2021 TABLE 4. Partnerships Leading to Significant Progress in Vaccine Delivery to the Field

For more than a century, sub-Saharan Africa has been affected by meningitis outbreaks, with as many as 450 million people at risk. The hope of a vaccine became a reality in December 2010, when Burkina Faso became the first of 22 African “meningitis belt” countries to introduce an affordably priced meningococcal A vaccine for less than 50 cents a dose. Working together, the World Health Organization, Program for Appropriate Technology in Health (PATH), Serum Institute of India, and the Bill and Melinda Gates Foundation partnered to successfully produce an effective and affordable vaccine to curb this annual epidemic. By the end of 2012, it became the first vaccine approved to be kept at up to 104°F (40°C) for 4 days, making deployment easy for the local environment and leading to the successful vaccination of more than 100 million people thus far.

Accounting for more than 450,000 deaths in children younger than 5 years, Rotavirus is responsible for an estimated 37% of all diarrheal deaths worldwide in this age group. Two vaccines are currently licensed for use: RV5 (Rotateq) and RV1 (Rotarix). Although these live attenuated oral vaccines have demonstrated lower efficacy in developing countries, they are expected to have a significant effect because of the high disease and morality burden. (18)(19) Costs of these vaccines can often be prohibitive for lower-middle-income and least developed countries to self-finance, especially with an increased number of countries being phased out for funding eligibility by the GAVI Alliance. The Indian government, Bharat Biotech, and PATH have teamed together to deliver a new low-priced rotavirus vaccine (Rotavac, US $3 for a 3-dose regimen), which has demonstrated reasonable efficacy in a recent phase 3 trial. (20) Although further testing and implementation in real field settings are still required, the significant price decrease for an efficacious rotavirus vaccine has the potential to expand access to many millions of children. The Meningitis Vaccine Project and the Rotavac collaboration are current examples of how successful collaborative efforts can bring together public and private entities to tailor an affordable vaccine suited for specific populations in need. (21)(22)

children, immunizations due, and vaccines received would programs. Streamlining systems within communities, allow information to be immediately available for better within districts, and nationwide can result in fewer missed program management from the health center to the national vaccinations, stronger public engagement, accurate demand level. Ideally, digitizing data at the point of contact with the forecasting, and stronger ability of policymakers to establish patient would minimize staff time, errors, and delays and and adapt vaccination strategies to their setting. maximize accuracy and scalability. Some fundamental ob- servations in the field that can assist in advancing these NEW DELIVERY TECHNOLOGIES information systems are outlined in Table 5. The use of text Safety messaging is even being piloted to monitor vaccine cold Because vaccine recipients are healthy at the time of admin- chain equipment to assess the benefits of remote alarm istration, any adverse event after immunization is highly systems over traditional temperature loggers. scrutinized. This concern is further intensified when taking Current information can provide limited coverage data, into account that hundreds of millions of children are stocking information from 1 to 2 months ago, but new immunized annually. As a result, rigorous safety evaluation systems will aim to provide up-to-date, pertinent data that measures will be applied to both the new vaccines and can influence day to day decisions in national immunization vaccine delivery technologies. An estimated 385,000 needle- stick injuries are reported by the CDC annually in US hospitals, whereas an estimated 2 million cases of needle- TABLE 5. Field Questions to Be Addressed With stick injuries occur globally, leading to considerable risk to Improved Information Systems health care practitioners. (24) Often, disposal of injection devices also serves as a challenge in resource limited areas. • Who are the unimmunized children? The WHO reports that approximately 16 billion injections B Which regions? B Can we find them? are given each year, with vaccination representing 5% of this • Where do we have the most wastage? total. Unsafe injection practices in poorer countries have B Why? • Does one district have enough stock? been attributed to 32% of hepatitis B cases, 40% of hepatitis B Is there enough to lend to another district for a short period? C cases, and 5% of human immunodeficiency virus infec- • fi If a speci c lot needs to be recalled urgently: tion cases. (25) New delivery methods offer simple to use B Where is it? B Who are the children who received it? devices that improve safety and minimize immunization logistics.

e36 Pediatrics in Review Downloaded from http://pedsinreview.aappublications.org/ by guest on September 23, 2021 TABLE 6. The Uniject Story: The Challenge of Vaccine Industry Adoption

Program for Appropriate Technology in Health, Patrick McKern. All rights reserved.

The Uniject system is a prepackaged, low-cost, easy to use, prefilled syringe that vastly reduces the amount of vaccines to be wasted. The autodisable injection system is a small bubble of plastic attached to a needle that allows health care workers to use it with less than 2 hours of training. Because it is precisely filled with the right amount and can only be used once, it ensures that the correct amount is delivered and reduces the risk of disease transmission due to needlestick injuries. Although this device was developed in 2000 and found to be cost-effective and beneficial for the use of tetanus toxoid and hepatitis B vaccines, only one vaccine producer commercially supplies vaccines in Uniject. (26)(27) (Program for Appropriate Technology in Health, Patrick McKern)

Prefilled and Autodisable Syringes search for alternative and easier methods that involve Inexpensive, single-use autodisable syringes have been needleless immunization. Current methods of needle-free licensed and available for commercial use since the early vaccination include cutaneous and mucosal immunization 1990s (Table 6). Support for safe injection practices mate- techniques (Figure 2). Increased costs of these vaccine rialized after a joint WHO and United Nations statement formulations must be weighed against savings gained with recommending the use of autodisable syringes by immu- decreased logistics, injection supplies, and hiring of skilled nization programs worldwide. (28) Prefilled autodisable personnel. syringes require no assembly or preparation and reduce vaccine wastage associated with multidose vials. These Intradermal Immunization preparations are especially helpfulforcommunityhealth The skin, a vital component of the immune system, is workerstobringalongontheirtripstopoorlyaccessed enriched with an efficient network of Langerhans cells, regions, where they can deliver the tetanus toxoid vaccine which take up antigen and subsequently stimulate systemic to pregnant females and the hepatitis B birth dose vac- (IgG and IgM) and mucosal (IgA) immune responses. (30) cine to their newborn infants, because most pregnant With reports of its use from the late 1930s, liquid jet females who live away from health centers deliver at injection is one of the oldest forms of needle-free immu- home. New autoreconstitution injection devices with nization. (31) Liquid jet injectors generate a highly pressur- dried vaccine are under evaluation. ized liquid stream that penetrates through the skin and can deliver all injectable vaccines at an intradermal, subcutane- Needle-Free Immunization ous, or intramuscular level. Because vaccine spreads Concerns about the large number of vaccinations in in- through a larger tissue volume compared with needle fantsandtoddlers,aswellasthesignificant problem of administration, jet injection may allow for a more pro- needle phobia in adolescents and adults, have driven the nounced and faster antibody generation before vaccine

Vol. 35 No. 7 JULY 2014 e37 Downloaded from http://pedsinreview.aappublications.org/ by guest on September 23, 2021 Figure 2. Various methods of needle- free immunization. (29) Reprinted by permission from Macmillan Publishers LTD: Mitragotri S. Immuniza- tion without needles. Nature Reviews Immunology. 2005;5(12):905–916, doi:10.1038/nri1728. 2005

degradation takes place. (31) These devices have had a long history of use and can deliver all injectable vaccines cur- TABLE 7. Liquid Jet Injection in the Global rently used in programs in developing counties at intrader- Context mal, subcutaneous, and intramuscular levels. Although the Disposable syringe jet injectors (DSJI) may play a critical role in global fi rst-generation syringe jet injectors could allow for a rate of polio eradication efforts. Inactivated polio virus (IPV) would likely 1000 immunizations per hour, they fell out of favor in the represent a preferred alternative to oral polio virus (OPV) because it is 1990s because of concerns of cross-contamination. These a killed virus and has demonstrated increased immunogenicity in fi areas where repeated OPV has failed to achieve adequate immunity injectors have since been modi ed to use disposable needle- in the community. Although IPV’s high cost (20 times higher than free syringes. At full production scale, disposable syringe jet OPV’s cost) remains a major obstacle, it would be preferred to OPV injectors may be comparable in cost to the current method if because it contains killed virus (no risk of vaccine-derived virus transmission) and has demonstrated increased immunogenicity in noninjectable delivery were to be decentralized via commu- areas where repeated OPV has failed to achieve adequate immunity nity health care workers, resulting in reduced program in the community. (32) costs. Although further evaluation is necessary to address • Investigators in Oman have found that using just 20% of the long-term protection, disposable syringe jet injectors could standard IPV by jet injection induced similar levels of seroconversion as intramuscularly administered IPV in 400 infants. (33) serve as an effective and feasible alternative to injectable • Although an earlier study in Cuba reported mild redness and formulations (Table 7). induration in some infants, (34) 93% of parents in the Oman study preferred the DSJI method because of the simple observation that “the baby does not cry.” Mucosal Immunization With 90% of microbial pathogens having a mucosal port of entry, mucosal vaccination offers protective immunity via locally secreted antibodies. In addition, these vaccines would be easier to administer, carry less risk of transmitting in- fection, and possibly simplify the manufacturing process, potentially increasing local vaccine production in developing countries. (35) Currently, internationally licensed mucosal vaccines used in humans exist for polio, typhoid fever, cholera, and rotavirus in oral forms, whereas one nasally administered influenza vaccine is being used in industrial- Disposable syringe jet injector use in action (Program for ized nations. Appropriate Technology in Health, Patrick McKern. All Because of its ease of administration, high patient com- rights reserved.) pliance, and long history of use, oral delivery of vaccines is an attractive mode of immunization. The main challenges

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e40 Pediatrics in Review Downloaded from http://pedsinreview.aappublications.org/ by guest on September 23, 2021 Closing the Global Immunization Gap: Delivery of Lifesaving Vaccines Through Innovation and Technology Sachin N. Desai and Deepak Kamat Pediatrics in Review 2014;35;e32 DOI: 10.1542/pir.35-7-e32

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