Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Technologies to Improve Immunization
NEW TECHNOLOGIES NEEDED TO REDUCE IMMUNIZATION LOGISTICS HURDLES
Immunization can be described as the process of delivering carefully packaged antigen to the appropriate destination in a vaccine recipient to produce a desired immune response. In this sense, immunization programs are package delivery systems: they manage the flow of antigens, which are formulated in vaccines and packaged in different presentations, between the point of origin at the vaccine manufacturer and the point of consumption, inside antigen-presenting cells (APCs) of the vaccinee. This simple concept of delivering antigen packages from point to point can help elucidate the complex logistical challenges inherent in the preservation, packaging, storage, transportation, and administration of vaccines.
Immunization is one of the most powerful tools for health, but many current vaccines are not affordable, accessible, and acceptable to everyone who needs them. Continual sharpening of this public health tool is needed to achieve the full potential of immunization for improving health. Some advances will come in the form of better vaccine antigens; however, the significant potential also lies in improving the way vaccines are packaged and delivered. Reviewing immunization as a package delivery process and recognizing critical hurdles, bottlenecks, and barriers to vaccine flow are initial steps toward making immunization programs more efficient and effective. Managing vaccine flow around those obstacles is the day-to-day work of immunization programs, which often requires heroic effort. This chapter briefly describes key restrictions to vaccine flow logistics in terms of complexity, cost, human resources requirements, distributability, and sources of errors in the immunization process. It reviews new technologies in various stages of development that have the potential to eliminate or reduce restrictions to vaccine flow. These new technologies have the potential to increase the capacity and efficiency of immunization programs and make immunization safer and more effective, affordable, accessible, and acceptable for everyone.
POINT-TO-POINT ANTIGEN PACKAGE DELIVERY
The four key points in the antigen package delivery system are the point of origin, storage and distribution point, the point of care (POC), and the final destination point in the recipient. The points of origin are the dozens of vaccine manufacturing plants where antigens are produced and, along with other components, formulated into vaccines, and where the vaccines are further packaged in multiple layers of containers for storage and distribution. The distribution and storage points form the network of thousands of sites from vaccine plants through national, regional, and local centers tasked with safely storing and transporting vaccines to the POCs. The POCs are the millions of hospitals, clinics, health posts, and homes where a competent vaccinator, an informed and willing vaccinee, and a safe and effective vaccine can be brought together for vaccine administration. The final destination points for antigen package delivery are the APCs inside the intramuscular (IM), subcutaneous (SC), cutaneous, or mucosal tissues of the billions of people who will benefit from immunization. Each of the four points along the package delivery system has distinct logistical challenges.
Points of Origin: Vaccine Manufacturing Plants
Purity and Stability
The antigen package delivery system originates in the vaccine manufacturing plant. The formulation, manufacture, and packaging of vaccines are well described in Chapter 6 ; this chapter highlights key factors relevant to immunization logistics. Vaccine manufacturing plants are highly capitalized, multimillion-dollar facilities that use sophisticated technology to mass-produce the billions of doses of vaccines used globally each year. Two critical vaccine flow logistics requirements start in the plant and span the entire immunization process up to vaccination of the individual: (1) maintenance of vaccine purity and (2) maintenance of vaccine potency by keeping it within the prescribed temperature range. These impose significant restrictions on vaccine flow logistics.
To maintain purity, the vaccine plant environment is highly regulated and monitored: people, equipment, and materials are introduced into the facilities in a precisely controlled manner. Expensive, high-speed filling equipment enables sterile packaging of bulk vaccines into specific-dose packages at low costs. Each step is carefully orchestrated, and even minor modifications to procedures or material may require approval from national regulatory authorities. Any change to the process implies regulatory consequences with significant associated economic costs (see Chapter 5 ).
For almost all currently licensed vaccines, the required storage conditions include constant maintenance at 2°C to 8°C (or −20°C for several vaccines). This requirement, which is met by the system known as the cold chain, constricts the flow of vaccine to facilities and delivery mechanisms that have refrigeration or cold pack storage capabilities. Some vaccines, especially those that include aluminum adjuvants, are susceptible to damage from freezing temperatures. Others, especially live-attenuated vaccines, are more susceptible to loss of potency at elevated temperatures. Through the addition of stabilizers and, in some cases, the additional step of lyophilization (freeze-drying), vaccines maintain minimum potency under the required storage conditions, throughout the listed shelf life. When breaks in the cold chain are detected, valuable vaccines are discarded. When undetected, cold chain failures can result in the administration of ineffective vaccine.
Presentation
Vaccine presentation affects flow logistics. In contrast to many pharmaceuticals, the majority of currently licensed vaccines are administered as liquids—by needle and syringe injection, oral delivery, or nasal spray. Most vaccines are formulated, packaged, and shipped as liquids in single- or multi-dose vials or prefilled syringes. All others are first formulated as liquids and then lyophilized to enhance their stability. Aside from one live oral typhoid vaccine that is packaged in an oral capsule filled with lyophilized vaccine, lyophilized vaccines are typically packaged in vials and require reconstitution. These lyophilized vaccines must therefore be accompanied by a liquid diluent and reconstituted before on-site filling of the administration device and vaccination. Liquid diluents increase the volume and weight of the vaccine, which may increase shipping costs and require more cold chain storage capacity. There are also the risks of spilling and leakage. Thus, the lyophilized format of vaccine with liquid diluent can slow down efficient vaccine flow.
There are three basic vaccine presentation schemes: prefilled delivery devices, liquid vaccine in vials or ampoules, and lyophilized vaccine in vials. Prefilled delivery devices simplify the logistics at the POCs because they minimize on-site preparation. They also reduce the number of components to be shipped; eliminate the need for a separate supply chain for vaccine, diluent, and administration devices; and reduce overfill required for vials and ampoules. However, packaging vaccines in prefilled delivery devices results in a higher cost per dose, and the larger volumes of some devices increase the space needed in cold chain storage.
Liquid vaccines packaged and shipped in vials or ampoules typically cost less per dose and occupy less cold chain space than prefilled vaccine presentations, but they require filling of the administration device at the POCs. This increases delivery complexity and creates an opportunity for human error, such as withdrawing the wrong dose amount from the vial or contamination of the vaccine due to improper aseptic technique or not following infection control practice. Vaccines in vials can be in single- or multidose format, with some multidose-format vaccines containing a preservative. Multidose vials typically cost less per dose and occupy less cold chain space than single-dose vials; however, vaccine wastage may be increased with multidose vials if a vial is opened and cannot be fully used within the allotted time frame specified by the manufacturer. Vaccinators also may be reluctant to open a 10-dose vial if only one or two people need vaccine, leading to missed opportunities to vaccinate those people. Repeated entry into a multidose vial and time-lapse between vaccine withdrawals increase the risk of bacterial or fungal overgrowth, with subsequent injection of a contaminated vaccine. Single-dose vials avoid some of these problems but cost more per dose, occupy more cold chain space, and still require on-site filling of the delivery device.
Lyophilized vaccines can be packaged in single- or multidose vials, and they share the same problems as liquid vaccines in vials. The reconstitution step needed for lyophilized vaccines adds further complexity to delivery, creating the opportunity for human error such as the use of a wrong amount of diluent or the wrong diluent. Other challenges with reconstitution include the potential for mismatched amounts of dry vaccine and diluent—which can be inadvertently shipped and stored separately, with vaccine in the cold chain and diluent at ambient temperature. This may lead to user confusion, depending upon the specific vaccine and manufacturer instructions for diluent storage and use for reconstitution. However, lyophilized presentations impart better stability and longer shelf life, especially for live-attenuated vaccines.
Inability to overcome the challenges presented by liquid, multidose-vial presentations and by lyophilized presentations can result in failure to immunize a vaccinee; cross-contamination of infectious pathogens among persons receiving vaccinations; and adverse reactions, including local abscesses, toxic shock syndrome, or even death. Although rare, these errors can have grave consequences and may significantly undermine public confidence in vaccines. Contemporary examples of reconstitution errors include an incident in Syria in 2014, when an anesthetic agent was mistakenly used for a vaccine diluent, resulting in 15 infant deaths and many hospitalizations. More recently, reconstitution error with an incorrect diluent led to the deaths of two children in Samoa in 2018 following measles, mumps, and rubella (MMR) vaccination, which subsequently led to decreased public confidence in MMR vaccination and a deadly outbreak the following year.
Distribution and Storage Points
Complex networks of storage and shipping facilities manage the distribution of vaccines from dozens of manufacturers to millions of POCs. The challenges associated with timely ordering, purchase, inventory, and monitoring are staggering and result in ongoing attempts to improve immunization programs and develop software to assist with the logistics.
Vaccine distributability, a key logistics concept, is how easily a vaccine can be transported to POCs and administered to vaccine recipients. Cold chain requirements at every level of storage and distribution can significantly reduce vaccine distributability. In general, the complexity and difficulty associated with cold chain management increase with distance from the manufacturer. It is relatively easy to keep large quantities of vaccine refrigerated and monitored in cold rooms at vaccine plants or large national or regional storage facilities, and economies of scale reduce the per-dose cost of storage. However, maintaining the refrigerated storage with around-the-clock monitoring and backup energy sources for the smaller quantities of vaccine present at each district and at the local level can be a daunting task. The new messenger RNA–based COVID-19 vaccines require storage at frozen or even “ultra” cold temperatures, as low as −80°C.
Package shipping must avoid delays that could allow vaccine temperatures to rise. Transporting vaccines at cold temperatures at the end of the cold chain, where transport is often by unrefrigerated vehicles, requires insulated boxes with cold packs, which significantly increase weight, expense, and difficulty.
Vaccination by needle and syringe injection requires highly skilled staff, which combined with limited staff supply can restrict distributability. Self-administered vaccines could significantly increase distributability, but only oral typhoid vaccine has been approved for self-administration. Other vaccines, such as the oral cholera vaccine, have been successfully assessed in resource-constrained settings for home administration after the first dose. Thermostable, self-administered vaccines distributed through regular mail systems are a conceptual example of ideal distributability.
Points of Care: Vaccine Administration Settings
The POCs are the settings where three essential components meet: vaccine, vaccinator, and vaccinee. Ideally, a caring and competent vaccinator administers a safe and effective vaccine to an informed and willing vaccinee. While this chapter focuses on the logistics of getting vaccines safely to the POCs and technologies for vaccine administration, getting vaccinators, and vaccinees to the POCs is equally important. As the complexity of the vaccination process increases, the skill level required of the vaccinator increases as well: safe parenteral injection requires highly trained staff, whereas oral vaccine delivery can be performed by minimally trained volunteers or by vaccinees themselves. Many pharmaceuticals and other treatments can be self-administered, but oral typhoid is currently the only vaccine approved for self-administration. Self-vaccination—enabling the vaccinee to be the vaccinator—could overcome the substantial logistical bottleneck resulting from skilled vaccinator shortages.
Getting potential vaccinees to the POCs can also be difficult, so these places need to be as close and convenient to everyone who needs vaccines as feasible. The vaccinee’s home may be the most convenient POC, and many mass-immunization campaigns in low-resource settings are conducted house to house to achieve maximum coverage. However, logistical challenges increase with rising numbers of POCs and with distance from distribution points. Vaccine hesitancy resulting from misinformation, lack of confidence in vaccines or the health system, complacency about the risk of vaccine-preventable disease, or inconvenience of immunization can be another limiting factor in getting potential vaccinees to the POC. This is a multifaceted problem that must be addressed at many levels. , This has been particularly evident during the COVID-19 pandemic, in terms of public perceptions, attitudes, and willingness to receive vaccination. , The pain associated with injection and needle phobia are issues that may cause people not to seek vaccination. Many adults and children suffer from needle phobia. , , Needle-free vaccine delivery technologies may increase the acceptability of vaccination.
Vaccination, vaccine delivery, and vaccine administration are all terms that may refer to the act of transporting a vaccine across the skin of the vaccinee into the cutaneous, SC, or IM tissue or into an orifice to contact mucosal tissue. The vaccine delivery systems used for administration, such as injection by needle and syringe or jet injectors, or application of microarray patches, may be considered macrodelivery systems. In contrast, vaccine microdelivery systems are the molecular antigen packaging technologies, such as viral vectors, microparticles, or virus-like particles (VLPs), that help transport the antigen to APCs once it has been administered to the vaccinee. Currently, most vaccines are administered by needle and syringe injection into the IM, SC, or intradermal (ID) tissues. Macrodelivery also includes vaccines that are delivered to mucosal sites by the oral, buccal, sublingual (SL), or intranasal (IN) routes in the form of liquid drops, sprays, or fast-dissolving tablets. Vaccine administration methods and devices are critical aspects of immunization logistics, and many of the new immunization technologies described in this chapter focus on vaccine macrodelivery systems.
Current Vaccination Methods: Description and Logistical Hurdles
Vaccination by Injection
Hypodermic injection with a needle and syringe dates back to the mid-19th century and is such a predominant vaccine administration method that “shots” or “jabs” are often considered synonymous with vaccinations. Mass production of needles and syringes results in extremely low costs for these devices. Injection breaches the skin’s stratum corneum, the protective layers of dead keratinized epithelial cells, to deposit vaccine in direct contact with the underlying dermal, SC, or muscle tissues. IM and SC delivery of vaccines by needle and syringe provides highly consistent dosing. For ID injection, because the dermal layer is so thin, precise targeted deposition is more difficult, so ID needle injection may provide less consistent delivery to the targeted tissues. Overall, needle and syringe vaccination produces excellent immune responses and is extremely safe when proper procedures are followed by trained vaccinators.
However, significant logistical limitations are inherent in needle and syringe injection. The high level of skill required for safe injections limits the availability of vaccinators. Reuse of contaminated syringes and needles for medical injections is common in some low- and middle-income countries (LMICs) and can lead to transmission of bloodborne diseases such as hepatitis and HIV. Inexpensive autodisabling syringes and needles can prevent reuse and mitigate this problem and have been widely adopted for use in vaccination. However, while autodisabling or reuse-prevention syringes are used in many countries, risk of needlestick injuries to healthcare workers remains a concern and increases healthcare costs. Safety-engineered syringes that include needlestick protection features, described later in this chapter, can reduce the risk of needlestick injuries and are widely used in high-income countries. Finally, the cost and complexity of safe disposal of sharps in the medical waste stream represent major logistical challenges.
To overcome many of the difficulties of needle and syringe injection, multiuse nozzle jet injectors (MUNJIs) were widely used in decades past for IM and SC injection—especially for mass-immunization campaigns. However, repeated use of the jet injection nozzles without cleaning between patients was shown to have a risk of transmission of bloodborne pathogens, and use of these devices was discontinued. Disposable-syringe jet injectors (DSJIs) eliminated this contamination problem and are discussed in detail later in this chapter.
Mucosal Vaccination
In addition to vaccination by injection, current macrodelivery methods include mucosal vaccination via oral ingestion or nasal spray delivery. Both methods share the advantages of being needle-free and present the possibility for self-administration and at-home delivery, which could reduce the burden on healthcare systems.
Mucosal vaccination mimics the route of entry, through portals to mucosal tissues, of many infectious agents and typically provides higher levels of protective mucosal immunity. Mucosal immune responses are important because the pathogen-specific antibodies that are stimulated by mucosal vaccination get secreted into the mucus where they can then neutralize pathogens at the site of entry even before they can cause infection.
The major challenge of mucosal vaccination is that delivery of antigen to the target tissues can be much less consistent than IM or SC vaccination by injection. Mucosal vaccination deposits vaccine on internal surfaces of the body. Although the vaccine is inside the body, it still must evade a variety of defense mechanisms to penetrate the mucosal surface and contact target tissues. Mucus flow, gastric acid, mucosal antibodies, and other antimicrobial substances continually destroy or remove substances on mucosal surfaces. As a result, mucosal vaccination generally requires higher doses of antigen, novel macrodelivery technologies to facilitate sufficient tissue contact time, and more specialized antigen microdelivery packaging to reach APCs consistently.
Destination Points: Inside the Vaccinee’s Antigen-Presenting Cells
Vaccination delivers the antigen package into the person receiving the vaccine, but delivery is not complete until APCs internalize the antigen. Immunization involves mimicry: vaccines must never be pathogenic but must cause the APCs to respond to antigens as pathogens. One of the first principles of this mimicry is that the antigen package should be “pathogen-like.” Free antigen in solution is typically ignored by immune cells; however, APCs readily take up microparticle packages that are in the size range of pathogens, such as viruses and bacteria, by phagocytosis and endocytosis. These microparticle antigen packages are likely to be assessed as threatening and to initiate an immune response. Molecular antigen packages may include adjuvants, which are nonantigen components designed to trigger or modify an immune response. Some adjuvants act as package “warning labels” to alert activation of the innate immune system. Other adjuvants create a depot effect, which causes the antigen package to be opened gradually, prolonging the presence of antigen at the delivery site. Another molecular antigen packaging strategy is the inclusion of specific cellular address labels. Typically, vaccine macrodelivery systems place the molecular antigen package in or near the tissues where APCs reside or traverse. For some vaccines, using molecules that match receptors on APCs, such as dendritic cells or microfold (M) cells, increases the likelihood of delivery specifically to these cells. Many molecular packaging strategies for antigen delivery that are in use or in development are described in detail in Chapter 67 , “Technologies for Making New Vaccines” and Chapter 68 , “Development of Gene-Based Vectors for Immunization,” and examples are described briefly later in this chapter. Once the APCs have received the antigen package, the next step is processing of antigen and presentation to lymphocytes to initiate the immune response, which is well described in Chapter 2 .
Logistical Hurdles in Special Settings
Low- and Middle-Income Countries
In LMICs, national immunization programs typically provide the vaccines recommended by the World Health Organization (WHO) for the following diseases: diphtheria, hepatitis B, Haemophilus influenzae type b (Hib), human papillomavirus (HPV), measles, pertussis, pneumococcal disease, poliovirus, rotavirus, tetanus, and tuberculosis. , For routine immunization, vaccines can be administered at health posts or clinics (fixed post), or in communities through mobile outreach on a daily, weekly, or monthly schedule. Many countries now also provide vaccines against meningitis and other pathogens. Supplemental immunization activities include mass campaigns that can be fixed-post (often including extra posts), mobile outreach, or house-to-house campaigns. Three critical immunization delivery hurdles in LMICs are the cold chain requirement, the need for skilled vaccinators, and sharps safety.
Most vaccines require refrigerated (2°C–8°C) cold chain storage and a few, including some first-generation Ebola and COVID-19 vaccines, require frozen (−15°C to −25°C) or ultra-cold chain (−60°C to −80°C) storage. Such requirements are especially challenging in countries with high ambient temperatures or with unreliable access to electricity. , Keeping vaccines tethered to refrigeration limits the capacity to distribute them to everyone in need because transporting them to remote locations requires insulated cold boxes and carriers many times larger and heavier than the vaccine itself.
Investments in strengthening vaccine cold chain systems, such as the Cold Chain Equipment Optimization Platform, are providing new cold chain equipment that is more reliable than older-generation equipment. These investments have increased cold chain storage capacity at lower health system levels in countries where the new equipment has been deployed. National-level storage, typically using walk-in cold rooms, is limited in many countries, which restricts the ability to store a surge capacity of vaccines for emergency campaign use during an epidemic or pandemic.
Some heat-stable vaccines have received regulatory approval to allow them to be managed outside the cold chain for limited periods of time. For example, a major reason for the successful meningitis A vaccine (MenAfriVac) campaigns in Africa was the modification of the storage requirements in a number of countries for the last miles of delivery. In these countries, a controlled temperature chain (CTC) was implemented, allowing the vaccine to be shipped and stored at ambient temperatures not exceeding 40°C for up to 4 days immediately prior to administration. In addition to increasing access to difficult-to-reach areas, economic studies estimate that CTC use could potentially reduce cold chain and associated logistics costs. , , , Two additional vaccines, an HPV vaccine (Gardasil 4) and an oral cholera vaccine (Shanchol), have subsequently been qualified for CTC use of different durations that are appropriate to the stability of the vaccines; others are forthcoming and will enable additional impact studies.
The second hurdle for immunization programs in many LMICs—and often the rate-limiting factor—is the shortage of skilled vaccinators. There is a global shortage of all healthcare workers, and safe and effective vaccination requires highly skilled workers for many vaccines, particularly for needle and syringe injection. Needle-free vaccines that could be administered by minimally trained staff or volunteers, or that could be self-administered, would significantly increase vaccine delivery capacity.
The third important logistics factor for immunizations in LMICs is sharps safety. Needlestick injuries are common; however, unlike in high-income countries, needlestick protection devices and postexposure prophylaxis to prevent bloodborne disease transmission following these injuries are often not available in low-resource settings because of cost. Safe disposal of used needles requires an expensive biowaste disposal infrastructure that is not always present. In some countries, used needles are harvested from the common waste stream and repackaged to the unsuspecting for reuse, presenting a high risk for transmission of bloodborne pathogens.
In the long run, thermostable, needle-free vaccines could significantly reduce each of these logistical hurdles to vaccine delivery and extend the benefits of immunization to all people. In the short term, intermediate technologies that are in development can improve cold chain shipping and storage and provide needlestick injury protection. Initiatives are also underway to accelerate the development of vaccine product innovations that can better meet the needs of LMIC immunization programs and achieve immunization coverage and equity goals. For instance, the vaccine innovation prioritization strategy (VIPS) initiative—which is led by an alliance of Gavi, the Vaccine Alliance (Gavi), WHO, United Nations Children’s Fund (UNICEF), PATH, and the Bill & Melinda Gates Foundation—developed an integrated framework to assess, prioritize, and advance vaccine product innovations. In May 2020, the process identified three prioritized innovations (microarray patches, heat-stable, and CTC-qualified vaccines, and bar codes). Action plans to accelerate uptake and impact are under development by the VIPS Alliance.
Emergency, Bioterror, and Pandemic Situations
Preparation for emergencies should be included in every national immunization program plan. The COVID-19 global pandemic represents the greatest common emergency that countries have had to navigate in terms of preparedness. The Coalition for Epidemic Preparedness Innovations (CEPI) was created in 2017 to advance both the development of and access to vaccines in response to global outbreaks. CEPI has worked to align and focus global stakeholders and nations through the COVAX Facility on both the development of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as well as work toward more programmatically suitable presentations of the vaccines. As these vaccines have been deployed, the readiness of countries has been challenged.
National programs had varying degrees of success in achieving high routine vaccine coverage rates prior to the global pandemic. There are concerns that the immunization coverage and, more broadly, health equity gains achieved to date will be negated by the challenge of dealing with the pandemic.
Special situations and high-risk populations increase immunization logistical challenges and create the need for rapid delivery of vaccines to vastly increased numbers of people. War and other armed conflicts interrupt routine vaccination services and displace large populations away from available services, often concentrating people in refugee settings that significantly increase the risk of disease and the need for vaccines. Natural disasters such as earthquakes, tsunamis, or hurricanes disrupt local infrastructure, including transportation, electricity needed to maintain the cold chain, and vaccine supply. Emergency situations expand the demand for skilled vaccinators and often diminish their supply, as vaccinators are personally affected by the emergency or pulled to other emergency duties. Reducing logistical barriers to routine vaccine delivery is critical to ensuring that the barriers are not insurmountable in an emergency situation.
In the event of a pandemic or bioterror event, local, regional, and even national healthcare resources and infrastructure may be overwhelmed, as has been seen in the recent SARS-CoV-2 pandemic. From an immunization logistics perspective, key factors to mitigate this will include ensuring vaccine and syringe supply and distribution, establishing accessible POCs for large numbers of people, and providing sufficiently skilled vaccinators to meet the vaccine demand. The United States—used here as an example of a high-income country—has a relatively strong immunization program infrastructure, which is reflected in high vaccination coverage rates (except for certain communities where vaccine hesitancy has led to historically low coverage rates). In the United States, POCs include doctors’ offices, health clinics, and, within the last several years, pharmacies. However, in an emergency, new vaccination POCs may be established—such as sports arenas, schools, convention centers, and other nontraditional locations—to allow mass vaccination to reach large populations rapidly. , , In a pandemic setting or a bioterror event involving an infectious agent, gathering masses of people in central locations for vaccination may represent an increased risk for transmission of the disease; thus, more discrete methods of vaccine distribution may be preferable.
The International Coordinating Group on Vaccine Provision as well as some national governments maintain supplies of key vaccines and coordinate distribution to respond to outbreaks. In response to COVID-19, the COVAX Facility was formed to pool procurement and equitable distribution of vaccines globally. WHO has published a target product profile with preferred and minimally acceptable characteristics of COVID-19 vaccines. Distribution of vaccines, injection devices, and other necessary supplies will be an immense undertaking given the global nature of this pandemic. Cold chain logistics are a critical consideration, as massive increases in vaccine volumes or atypical storage requirements (such as ultra-cold chain storage) can overwhelm countries’ cold chain capacity. Equitable access and prioritization of at-risk individuals are key considerations and depend on the nature of the outbreak disease. For COVID-19, high-priority populations include healthcare and other essential workers, the elderly, people with preexisting conditions, and the socially disadvantaged, among other groups.
Summary: Desirable Features of Practically Ideal Vaccine Delivery Systems
The major immunization logistical challenges to vaccine flow include the following: distribution of multicomponent products, purity and sterility requirements, cold chain requirements, availability of highly skilled vaccinators, on-site filling and reconstitution, needle safety issues, and transfer of antigen into APCs.
Technologies described in this chapter address some or many of these challenges. Overall, a practically ideal vaccine delivery system would be a thermostable vaccine in a prefilled unit dose for needle-free delivery with minimal waste. The vaccine would be optimized for shipping, even by mail in some cases, and would be self-administered or administered by minimally trained personnel. The molecular antigen packaging would ensure safe delivery of the antigen into the APC and induction of the immune response with minimal adverse reactions.
NEW TECHNOLOGIES FOR VACCINE STABILIZATION, PACKAGING, STORAGE, SHIPPING, AND ON-SITE PREPARATION: POINTS OF ORIGIN AND DISTRIBUTION POINTS
Maintaining the integrity, potency, and safety of vaccines from their point of origin at the vaccine manufacturer through the point of preparation and use requires attention to the vaccine’s formulation, packaging (primary, secondary, and tertiary containers), and preparation.
Formulation
The development of vaccine formulations includes the chemical and physical characterization of the antigen, potency assays for lot release and to demonstrate stability, preclinical and clinical evaluation of the optimal administration route to include the potential use of adjuvants, and formulation stability development. Current live-attenuated vaccines are not formulated with an adjuvant. Nonreplicating vaccines that include inactivated viruses and bacteria, VLPs, carbohydrate antigens, and purified or recombinant subunit protein antigens are typically presented as liquid solutions or suspensions and usually contain adjuvants to induce the desired immune response.
A vaccine’s formulation consists of the antigen as well as the other supporting ingredients, called excipients. Excipients include stabilizers to maintain vaccine stability, preservatives to prevent microbial contamination, and adjuvants to enhance potency. A carefully developed formulation can also increase the thermostability (resistance to high ambient temperatures or freezing) of the vaccine and avoid damage to the antigen due to freezing or high temperatures. Live-attenuated vaccines are often lyophilized and freeze stable but tend to rapidly lose potency after reconstitution. Nonreplicating vaccines can be more stable in high temperatures compared with live-attenuated vaccines but can also be damaged by freezing, particularly if they include aluminum adjuvants.
Preservatives
Thimerosal, an organic mercury preservative (containing approximately 50% mercury by weight), is used in some inactivated vaccines for multidose-vial formats to prevent microbial growth in opened and partially used vials. It is also used during some vaccine manufacturing processes as an inactivation agent. Thimerosal is intended to kill or prevent the growth of a broad spectrum of pathogens (bacteria, fungi). The safety of thimerosal has been evaluated by the Global Advisory Committee on Vaccine Safety as well as other national-level expert groups and regulatory bodies, such as the European Medicines Agency, the American Academy of Pediatrics, and the US Food and Drug Administration (FDA). These evaluations concluded that given the short biological half-life of ethyl mercury—which is excreted via the gut and does not accumulate in the body—evidence of long-term toxic effects has not been demonstrated. In 1999, however, the US Public Health Service urged vaccine manufacturers to reduce or eliminate thimerosal from vaccines as a precautionary measure. Currently in the United States, routine vaccines are thimerosal-free or have levels less than or equal to 1 µg of mercury per dose. Two other preservatives in WHO-prequalified vaccines are 2-phenoxyethanol, which is used with inactivated poliovirus vaccine (IPV), and phenol, which is used for inactivated typhoid vaccine.
Many industrialized countries, such as the United States, have switched to single-dose vials for use in routine immunization; thimerosal is not used because the vial is accessed only once. However, in multidose vial formats for seasonal influenza vaccines and vaccines for epidemic or pandemic response, preservatives such as thimerosal continue to be used. Furthermore, many vaccines used in LMICs still contain thimerosal, including diphtheria, tetanus, and pertussis (DTP); hepatitis B; Hib; influenza; and meningococcal vaccines. LMIC use of single-dose vial presentations is limited by vaccine manufacturer production capacity, the increased cold chain volume, and cost, which many countries cannot absorb.
Thermostability
Extended exposure to elevated and freezing temperatures—those temperatures outside of the recommended range (normally 2°C–8°C)—can damage vaccines. Heat can denature or otherwise alter the protein tertiary structure; this may reduce viability of live-attenuated vaccines or, in the case of polysaccharide conjugate vaccines, result in increased rates of hydrolysis of the polysaccharide from the protein in the vaccine formulation. The formation of ice crystals can result in freeze damage to the antigen and freezing of vaccines that contain aluminum adjuvants can reduce potency from agglomeration of the adjuvant.
Thermostability could reduce potency loss and have positive impacts on vaccine efficacy. , It could also allow removal of vaccines from the cold chain, reduce costs, and lead to increased coverage by allowing flexibility in time to reach remote populations. Some thermostable products could be dry cakes similar to lyophilized vaccine and would require reconstitution prior to injection. Thermostable lyophilized products for mucosal administration could be used as is, simplifying administration logistics. Other dry formulations could be incorporated into unit-dose, dry-format delivery systems, such as microarray patches, or into dry-powder aerosols for respiratory administration (see the “Cutaneous Vaccination” and “Mucosal Vaccination” sections). These formats would have the combined benefits of being needle-free and thus simple to administer or self-administer. They would not require refrigeration or reconstitution.
Protection From High Ambient Temperatures
Enhanced thermostability of liquid formulation vaccines can be achieved through selection of buffering agents and by the use of excipients that can further stabilize the formulation. Examples include nonreducing sugars, nonionic surfactants, divalent cations, and polymers or protein stabilizers. Excipient stabilization can enhance protection from shifts in pH, decrease antigen loss as a result of surface adsorption and aggregation, and prevent or reduce protein-to-protein interactions.
Freeze Protection
Many vaccines, particularly those containing aluminum adjuvants, are sensitive to freezing. Propylene glycol, polyethylene glycol, and glycerol have been used to protect aluminum-adjuvanted vaccines from freezing. Various concentrations of propylene glycol have prevented vaccine freezing or loss of potency and have prevented destructive particle aggregation if physical freezing occurred. ,
Dry-Format Delivery
A modification to the lyophilization process has been explored for producing freeze-dried tablets for oral mucosal delivery of vaccines and pharmaceuticals. Furthermore, several feasibility studies have been conducted using the lyophilized tablet presentation with promising thermostability in this dry format. , Alternative processes to lyophilization under investigation for vaccine drying (removing water molecules from the vaccine suspension) include spray-drying, spray freeze–drying (SFD), vacuum foam–drying, and supercritical fluid–drying. These processes have been evaluated for increasing vaccine thermostability. Research with aluminum hydroxide–adjuvanted hepatitis B surface antigen (HBsAg) or HPV vaccines, as well as aluminum phosphate–adjuvanted diphtheria and tetanus toxoids, has been conducted using alternative freeze-drying processes. These studies have typically found aluminum coagulation and difficulty in reconstitution for lyophilized adjuvanted vaccines, although additional excipients and a thin film freeze-drying process may provide freeze protection. , The SFD method produced a homogenous suspension, indicating the feasibility of this approach for aluminum-adjuvanted vaccines. Evaluation of SFD of HBsAg without aluminum in combination with inulin or dextran/trehalose stabilizers demonstrated enhanced thermostability (up to 60°C). However, preclinical immunogenicity studies of this formulation demonstrated immunoglobulin (Ig) G immune responses that were lower than responses to aluminum-adjuvanted HBsAg. SFD has also been assessed for meningitis A and measles vaccines. ,
In addition, alternative delivery or packaging methods, such as dry-powder inhalation, microarray patches, biodegradable implants, or integrated reconstitution technologies (discussed later in this chapter), are currently being developed or used for biologics or pharmaceuticals and could be adapted for vaccines. Primary excipients include nonreducing sugars, such as trehalose or sucrose, because of the high glass-transition temperatures they exhibit. Glass (amorphous solid) is formed instead of crystals when these excipients are dried, which contributes to vaccine stability.
Packaging
Vaccine packaging is the collection of components that surround the vaccine and protect its integrity (potency/stability/shelf life) from production through the supply chain to the POCs. Vaccine packaging is typically divided into three categories: primary, secondary, and tertiary. , Primary packaging protects against light, oxygen, and moisture vapor ingress, and it must not allow pH shifts that could affect vaccine stability or antigen binding to the material of the container that could reduce the available dose. The packaging also provides information and identification of its contents. Labeling to identify the product must be integral to the packaging or affixed to it. Primary containers are nested together in secondary packaging, and larger containers such as boxes or cartons provide tertiary packaging.
Primary Packaging
Vial and Ampoule (Vaccine and Diluent)
Primary packaging, such as ampoules, vials, prefilled syringes, and prefilled oral dispensers, comes into direct contact with the vaccine product or diluent and may affect the vaccine formulation itself. WHO has issued programmatic suitability guidelines covering vaccine formulation, presentation, labeling, and packaging to ensure that vaccines submitted for prequalification have been optimized to address LMIC needs. These guidelines include mandatory, critical, unique and innovative, and preferred characteristics. Mandatory and critical characteristics must be met to achieve WHO prequalification. In the case of critical characteristics, some deviation from defined values may be allowed when taking into account public health needs. Unique and innovative characteristics may be vaccine specific and are reviewed as such. Preferred characteristics are not required, but they represent the buyer preference (i.e., procurement agencies and national immunization programs).
Vaccines must be WHO prequalified for purchasing by United Nations agencies. The WHO requirements on vaccine quality, safety, and efficacy are included in the prequalification process, as well as compliance requirements for manufacturing and specifications for packaging and presentation. Prequalification provides assurance that vaccines used by national immunization programs are safe, effective, and meet quality standards.
The Vaccine Presentation and Packaging Advisory Group (VPPAG) was a WHO- and UNICEF-led forum for both the public sector and industry to discuss and provide advice on vaccine presentations and packaging. VPPAG developed a generic preferred product profile for vaccines for LMIC use, which recommends “ready-to-use” presentations that do not require mixing (i.e., reconstitution) and formats that reduce the number of user steps (and potential errors). Vaccine formulations with improved heat and freeze stability also are recommended to provide for higher temperature storage (target threshold at 40°C) and potential use beyond the cold chain. Prefilled syringes or injection systems should reduce the volume required in the cold chain and should incorporate an autodisable feature that prevents reuse. These designs are designated as compact, prefilled, autodisable devices (CPADs). The generic preferred product profile also includes vaccine vial dimensional recommendations that conform to the International Organization for Standardization (ISO) standard ISO 8362 and are the most efficient size for the cold chain. Vial labeling should include a vaccine vial monitor (per UNICEF and WHO recommendations), which consists of a temperature-sensitive material and serves as a visual indicator of cumulative heat exposure. Labeling should also include standard product, date, and lot information, among other requirements. Many of these recommendations are reflected in WHO’s programmatic suitability requirements.
Unit-Dose Versus Multidose Formats
Multidose presentations are common in LMICs, a result of both lower cost and reduced per-dose volume compared with single-dose presentations. Industrialized or high-income countries are less vaccine-price sensitive and have generally switched to single-dose presentations for adult and childhood vaccines. The shift to single dose was accelerated by public concerns regarding thimerosal, healthcare provider preference for single-dose presentations including prefilled syringes, and increased awareness of injection safety. In the United States, the awareness of safety issues came in response to the Needlestick Safety and Prevention Act and subsequent revision of the Occupational Safety and Health Administration bloodborne pathogens standard. This led to requirements for workplace reporting and maintenance of a log of needlestick injuries as well as broader implementation of engineered safety features to reduce or prevent the risk of needlestick injury.
The use of single-dose and small multidose presentations also has increased in LMICs, in part because of the higher costs of vaccine wastage for newer vaccines. , The use of preservatives in multidose vials is critically important for vaccines that are used in more than one immunization session because repeated access of the vial through the septum as well as storage between sessions present potential contamination risk from pathogen ingress. WHO’s multidose-vial policy permits open vials of vaccine with preservative, which have been handled under specific conditions, to be used for up to 28 days after the first dose is withdrawn.
These policies apply only to liquid vaccines that contain preservative; lyophilized live-attenuated vaccines—such as measles-containing, bacillus Calmette-Guérin (BCG), and yellow fever vaccines—generally do not contain preservatives and must be discarded at a maximum of 6 h after reconstitution, per the multidose-vial policy. Because of vaccine wastage concerns, some healthcare workers are hesitant to reconstitute a multidose vial if there are insufficient numbers of eligible people to be vaccinated to use up all the doses in a vial, which can result in missed vaccination opportunities.
Preservative-Free Multidose Primary Packaging
Intact Solutions LLC, a subsidiary of MEDInstill LLC, a US-based firm, has developed a primary packaging and pharmaceutical filling and dispensing technology called Intact that may enable large (200- or 400-dose) multidose presentations of unpreserved vaccine. The technology is designed to reduce the risk of contamination during both filling and dispensing from a primary container and to minimize cold chain storage volumes. To maintain sterility during the filling process, a closed-system valve is used for the filling needle. The prevention of contamination allows for sterile filling in a non-aseptic facility. ,
In addition, the Intact design has been incorporated into the dispensing port for novel primary containers. The valve allows multiple withdrawals from the container through either a Luer port or a multidose syringe, maintaining sterility of the contents even in the presence of external contaminants. Multidose pouch designs ( Fig. 69.1 A) are undergoing evaluation for the mass delivery of pandemic vaccines.
Blow-fill-seal primary packaging
The blow-fill-seal (BFS) manufacturing method produces primary containers from polyethylene or polypropylene and is used for a variety of pharmaceuticals ( Fig. 69.1 B). The containers are extruded, blown, filled, and sealed in an automated, continuous process, and can be formed into ampoules or vials with a septum. Rommelag, Weiler Engineering, and Brevetti Angela are leading examples of BFS machine manufacturers. The first vaccine to be approved in a BFS container was GlaxoSmithKline’s oral ROTARIX vaccine ( Fig. 69.1 C). The design has individual containers conjoined by a shared tab. When one container is separated from the tab, it is rendered open and must be used to deliver the vaccine. This attribute provides key advantages compared with single-dose presentations, including cold chain volume reduction and potential cost savings. BFS has also been evaluated with other vaccines, including MedImmune’s live-attenuated influenza vaccine (LAIV) and Novavax’s recombinant respiratory syncytial virus F nanoparticle vaccine, and has been used commercially for packaging vaccine diluents. For parenteral vaccines, a needle and syringe could be used to withdraw a dose from a BFS ampoule or vial with an integrated septum, such as Catalent’s ADVASEPT Vial Technology ( Fig. 69.1 D), and prefilled BFS injection devices have been developed (see “Blow-Fill-Seal Prefilled Injection Devices” section below).
The manufacturing method of BFS containers distinguishes them from preformed plastic squeeze tubes that are injection molded or extruded, which have been developed primarily for oral administration. Preformed containers are manufactured, terminally sterilized, and shipped to the pharmaceutical manufacturer for filling and heat sealing. Examples are the Rexam dispenser tube, also used for packaging GlaxoSmithKline’s Rotarix vaccine, and the Lameplast tube, used for Merck’s RotaTeq vaccine (see Fig.69.1 E and F ).
Prefilled Syringes
Prefilled syringes represent a fully integrated vaccine presentation. Multiple studies comparing prefilled syringes with standard vial presentations have demonstrated increased efficiency and improved vaccination throughput with this packaging format. For example, a study of US nurses preparing and delivering influenza vaccine reported that the time necessary for providing an injection was 12.4 s for a prefilled syringe compared with 49.7 s for a multidose vial. The increased efficiencies possible with prefilled syringes for both parenteral and nonparenteral administration (oral/nasal) could greatly enhance pandemic/epidemic outbreak response capacity.
Glass Prefilled Syringes
Glass prefilled syringes are manufactured from type 1 borosilicate glass, which has high chemical resistance, low alkali content, and barrier properties appropriate for long-term storage of vaccines and other pharmaceuticals. A leading example is the Becton, Dickinson and Company’s (BD’s) Hypak SCF (sterile, clean, ready-to-fill) glass prefilled syringe that is used widely in the United States and Europe ( Fig. 69.1 G). This design comes in different models to include fixed-needle, Luer slip, and Luer-Lok varieties. Other manufacturers include Gerresheimer, SCHOTT, Nuova Ompi, Nipro, and Catalent. Glass has been used for decades for a variety of primary containers (prefilled syringes, vials, cartridges). Problems associated with its use include the weight of the container and the possibility of cracks or breakage.
Plastic Prefilled Syringes
Various plastic materials have been used as alternatives to glass for both prefilled syringes and other primary container technologies. Plastic syringes are injection molded, allowing for tighter dimensional tolerances and ability to generate alternative geometries. Plastic prefilled syringes are lighter in weight and more resistant to breakage than glass during production, fill/finish, shipping, and programmatic use. Polypropylene is a polymer used for standard- and large-volume prefilled syringes (up to 50 mL) and vials. Cyclic olefin copolymer and cyclic olefin polymer are highly transparent polymers that have been used increasingly for prefilled syringes. , Compared with polypropylene, cyclic olefin copolymer, and cyclic olefin polymer have lower water vapor and oxygen permeability, allowing long-term storage of vaccines, and have been demonstrated to be biocompatible (not harmful to living tissues), resistant to heat, and compatible with various terminal sterilization processes.
The selection of glass or plastic is determined by the formulation or stability requirements of the pharmaceutical, needs of the patient/user, and other requirements. Plastic prefilled syringes are typically more expensive than glass. Examples include the BD Sterifill SCF, SCHOTT TOPPAC, Gerresheimer ClearJect, Baxter Clearshot, and West Pharmaceutical Services, Inc. Daikyo Crystal Zenith ready-to-use, silicone-free syringes. Cyclic olefin copolymer and cyclic olefin polymer have also been used for vials; for example, Aseptic Technologies’ AT-Closed Vial, which is composed of cyclic olefin copolymer ( Fig. 69.1 H), was validated for use with GlaxoSmithKline’s Synflorix pneumococcal vaccine.
Compact, Prefilled, Autodisable Devices
A CPAD is a prefilled, single-dose injection system comparable to a prefilled syringe but with an autodisable feature that prevents reuse. Like prefilled syringes, CPADs provide accurate doses, fast injection preparation, and quick delivery time (ready to use). In addition, because they are typically smaller than standard syringes, they bring the logistical benefits of decreased volume and weight for transportation, storage, and disposal.
The BD Uniject injection system ( Fig. 69.1 I) is a CPAD technology with a small reservoir prefilled with vaccine or other pharmaceutical. It has four main components: reservoir, port, needle assembly, and needle shield. The reservoir is a three-layer laminate film with linear low-density polyethylene in contact with the contained fluid. The needle shield is removed from the needle for administration. Typically, a foil-laminate secondary pouch maintains stability of the material in the Uniject units. Crucell previously developed a novel multidose secondary packaging for the Uniject system that can store up to 20 filled devices. A needle-less version of the Uniject platform, designated the “Uniject DP,” also has been developed by BD for oral delivery. To deliver the prefilled dose, after removal of the needle shield and insertion of the needle, the plastic reservoir of the Uniject system is squeezed between the thumb and fingers. The container is provided sterile in “ready-to-fill” reels of 1500. The sterile reel is loaded onto a custom filling machine where the containers are filled and then heat sealed.
PT Bio Farma’s (Indonesia) hepatitis B and tetanus toxoid vaccines and Crucell’s Quinvaxem fully liquid pentavalent vaccine were previously WHO prequalified in Uniject, but only the hepatitis B Uniject is currently being produced. A time-and-motion study in Kenya comparing the average time for health workers to prepare and inject 20 doses of pentavalent vaccine in five different presentations found that the prefilled Uniject system was faster to deliver than fill-on-site presentations (single-dose or multidose vials, liquid or lyophilized).
The Injecto easyject is a recently developed CPAD alternative. It consists of a polymer prefilled syringe bell with an integrated needle. The needle cap also serves as the syringe plunger, minimizing packaging volume. The easyject device can be filled on traditional prefilled syringe production lines, and it is intended to be a lower-cost prefilled syringe option with an autodisable feature.
Blow-Fill-Seal Prefilled Injection Devices
For parenteral delivery, an interface can be incorporated into the neck of a BFS ampoule, allowing for connection of a needle to form a squeezable, prefilled injection device that capitalizes on the high production throughput of BFS technology. Brevetti Angela and Rommelag have developed BFS systems with integrated needles that are incorporated during the forming process ( Fig. 69.1 J). ApiJect has developed a prefilled BFS system with separate needles that are intended to be connected to the container by the user; it has advanced development and production capacity with US government funding for COVID-19 response ( Fig. 69.1 K). , In the future, it may be possible to integrate an autodisable feature into a prefilled BFS device, forming a novel, low-cost CPAD.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here