- Email: [email protected]
Technologies that make administration of vaccines safer
Vaccine 22 (2004) 2054–2058
Technologies that make administration of vaccines safer C. John Clements∗ , Gordon Larsen, Luis Jodar Department of Vaccines and Biologicals, World Health Organization, 1211 Geneva 27, Switzerland
Abstract There is an ever-expanding technology that is aimed at making the administration of vaccines safer. Conventional ways of administering vaccines are being upgraded, modified or replaced by a wide variety of innovations. The paradigm of liquid vaccines, needles and syringes is slow to change, but already developments are ocurring that will change for ever the way vaccines are administered and will improve the safety record of immunization. The oral route of vaccine administration has generally been thought of as safe, but until now only the polio vaccine has been widely used in this way. The conventional method of vaccine administration is by injection. Many ingenious devices have become available that now make injecting safer. Inventors are now looking imaginatively to alternative routes and technologies for delivering vaccines. Vaccines are genreally manufactured to extremely high standards and rarely are shown to be the cause of safety issues. People remain the weakest safety link is vaccine administration. Technologies that bypasses the ability of man to make bad decisions or to behave incorrectly are of tremendous value. The vaccine world is in the middle of a radical re-think about how vaccines might best be administered. The presentation of the vaccine can be altered to fit new technologies such as powder jet guns, or skin patches. Even the conventional needle and syringe have evolved to much safer versions, and are set to continue this evolution. All this means even safer vaccines and their delivery. © 2003 Published by Elsevier Ltd. Keywords: Vaccine; Oral polio vaccine (OPV); Immunisation; Reconstitution; Multi-dose vials; Recapping; Auto-disable syringe; Jet gun; Jet injector; Thiomersal; Trehelose; Oral/nasal administration; Skin patch
1. Introduction There is an ever-expanding technology that is aimed at making the administration of vaccines safer. Fortunately, this technology is not limited to vaccines but is applicable in varying degrees to other health care deliveries, and even to uses outside the human health field. However, the focus of this paper is to provide background information about safe vaccine administration that fits into wider discussions on how to make vaccines as safe as possible. The oral route of vaccine administration has generally been thought of as safe, but until now only the oral polio vaccine (OPV) has been widely used in this way. The conventional method of vaccine administration is by injection. Many ingenious devices have become available that now make injecting safer. Inventors are now looking imaginatively to alternative routes and technologies for delivering vaccines. We are entering a new and safer era of technology that is likely to transform radically the concept of vaccine and drug administration.
∗
Corresponding author. Tel.: +41-22-791-4402; fax: +41-22-791-4193. E-mail address: [email protected] (C.J. Clements).
0264-410X/$ – see front matter © 2003 Published by Elsevier Ltd. doi:10.1016/j.vaccine.2004.01.008
Adverse reactions may be caused by an intrinsic property of the vaccine, by a fault in the vaccine production, by an idiosyncratic response of an individual or by an error in handling or administration. Human error is the hardest to eliminate and is why so many technologies are aimed at bypassing the need for a particular human decision or behaviour. However, most adverse events reported to occur soon after vaccination are not reactions causally related to the vaccination process but are only coincidental events. With a wider possibility of techniques available comes a more complicated set of related choices. The selection of the most appropriate vaccine administration technology, the method of waste disposal, the number of doses of vaccine per vial and a number of other criteria are all inter-related challenges for the health service planner. 2. A wide spectrum of activities A safe vaccine is not simply one that has been manufactured, tested and found to be safe in clinical trials. Important as those aspects are, there are other possibilities for making immunisation safer. These include safe transport to the point of administration, safe administration, safe disposal of the vial and injection equipment, and post-marketing surveil-
C.J. Clements et al. / Vaccine 22 (2004) 2054–2058
lance to detect any unexpected reactions as soon as possible. Finally, even when everything is in place to ensure the safest possible vaccine and its delivery, if the perception of the pubic is that some facet of the system is not safe (no matter what the reality), the entire immunisation programme may be placed in jeopardy.
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constituted vaccine is kept outside the refrigerator. Contamination of reconstituted measles vaccine with Staphylococcus aureus has been documented in a number of countries [1–3]. Reconstituted vaccines should be discarded after 6 h or at the end of the session, whichever is sooner. A preservative such as thiomersal is used in multi-dose liquid vaccines to ensure organisms that accidentally contaminate the vaccine during multiple use are killed off quickly.
3. Safe manufacture Controls imposed on vaccine manufacture ensure a higher standard of production than ever before to the extent that it is extremely unusual to identify production errors as a cause of adverse reactions, even though it is usually the first thought in the public’s mind. The quality of vaccine products is controlled by the National Regulatory Authority (NRA), and batches are not released unless they are passed as having met the requirements of the control authority. Good manufacturing practice (GMP) must be established and maintained. The product must be of high quality and of consistently high quality. Once manufactured, the vaccine must be filled into vials in a way that maintains sterility. 4. Safe transportation—bench to bush A system of technology exists to ensure that the vaccine produced at the bench reaches the bush in the best possible condition. To monitor that correct temperatures have been maintained all the way from the factory, simple monitoring devices have been developed, vaccine vial monitors (VVMs), that are heat-sensitive labels attached to vaccine vials that change colour if temperature limits are violated. Initially, VVMs were used on the labels of oral polio vaccine vials. Now, all vaccines purchased by the United Nations have VVMs on them. Vials that have labels on which the VVM has changed to the wrong colour are discarded. Thus, vials with VVMs can now be used outside the cold chain for community outreach immunisation efforts so long as the VVM does not detect a temperature violation by a change of colour.
5.2. Injection technique training Improper administration of BCG vaccine may lead to BCG lymphadenitis in the lymphatic drainage near the site of the injection. This reaction has mainly been related to a change in vaccine strain without staff being made aware of the need to reconstitute with a different volume of fluid [4–6]. Needles inserted into the buttock to administer vaccines may pass close to the sciatic nerve. Irritant vaccines injected into or close to the nerve have been documented to cause paralysis in some instances. For this reason, careful training is needed to ensure vaccines are injected to the appropriate depth (e.g. intradermal for BCG, subcutaneous for measles vaccine, intramuscular for tetanus toxoid) and appropriate site (outer aspect of the thigh for infants in most cases, and tissue over the deltoid muscle for older children and adults). 5.3. Storage Vaccines must be maintained at the correct cool or cold temperature during transport and storage as well as after reconstitution and during use. Their shelf life (generally 2 years) must not be exceeded. In some health centres and hospitals, potentially dangerous medications may erroneously be kept in the same refrigerator as vaccines. These medications may be packed in vials or ampoules that resemble vaccines or their diluents and may be used by mistake for reconstitution of EPI vaccines. Mistaken use of a muscle relaxant drugs (pavulon or anectine) or insulin were incriminated in several instances, all of which resulted in infant deaths [3].
5. Safe administration
5.4. Recapping needles
5.1. Reconstitution and multiple dose vials
If the vaccinator replaces the cap over the needle after use, there is a high probability that in the process, he will stab himself with the needle tip sooner or later. If the body fluids on the needle are infected with a hepatitis virus, human immunodeficiency virus or other pathogen, the operator may become infected. Accidental needle-stick has become a major public health problem. Studies in Western Europe and the USA showed that as much as 87% of health workers under-report needle-stick injuries [7]. WHO recommends that needle recapping should not be undertaken but that the syringe and needle should be disposed of immediately after use into a “sharps box” or other secure container.
While freeze drying of vaccines makes for an excellent method of vaccine manufacture and long-term storage, it also provides an opportunity for human error at the point when it is reconstituted back into a liquid. For example, unsterile procedures during reconstitution or inadequate storage and use of reconstituted vaccine over a number of immunisation sessions are likely to result in contamination of the vaccine. BCG vaccine has no preservative at all and measles vaccines contain limited amounts of antibiotics. Therefore, rapid multiplication of pathogens can take place, especially when re-
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5.5. Equipment Syringes and multi-dose vials are the main elements of the delivery system for immunisation services in developing countries today, accounting for 80% of the vaccines administered globally. Of the 12 billion syringes sold each year for medical injections, only 5% (around 1 billion) are used for vaccines. Yet the number of antigens routinely administered is increasing rapidly and it is anticipated that the number of injections will increase further [8]. Worryingly, a substantial number of the injections administered world-wide are not administered in a way that can guarantee sterility. A WHO-sponsored review [3] of unsafe injection practices in the developing world showed that at least 50% of all injections were unsafe in Asia, sub-Saharan Africa and the former Soviet Republic, exposing patients to the risk of infection from hepatitis, HIV or other blood-borne pathogens [9–11]. Syringes and needles are widely re-used in developing countries because of scarcity, re-sale value and a cultural resistance to waste. More than 30% of immunisation injections may be unsafe, primarily due to re-use [12]. In developing countries, the conditions of work are arguably more difficult and extreme. For example, over half of the injections for immunisation are provided with sterilizeable syringes and needles, items that must be handled and cleaned individually before sterilisation. 5.6. Safe technologies While current vaccine administration techniques are well tested, their simplicity and safety profiles can be much improved. Designing systems that are simpler and less prone to adverse events, regardless of the human factor, are therefore very attractive. The current biotechnological revolution, together with increased knowledge about immune responses, are promoting the construction of new delivery systems and technologies that may revolutionise immunisation programmes beyond recognition. 5.6.1. Auto-disable syringe The preferred syringe for mass immunisation campaigns is now the auto-disable (A–D) syringe [13]. This syringe has been tested both in the laboratory and field [14], and has been shown to be easier to use and preferred by the health worker. Overall, the A–D syringe contributes to decreased blood-borne pathogen transmission between patients by preventing re-use and re-sale, both common practices in developing countries. In a field trial in Indonesia, the SoloShot® A–D syringe delivered more precise and consistent doses and 15% more doses per vial than disposable syringes [15]. 5.6.2. Preservatives Multi-dose vials have been the standard presentation of the majority of vaccines used in developing countries.
WHO’s current policy [16] allows certain multi-dose vials to be used over a period of a month to control wastage and ensure the administration of vaccine when only a few children attend each vaccination session. Multi-dose vials of liquid vaccine need the presence of a preservative in them to ensure sterility once the vial has been opened. The commonest preservative is thiomersal, a mercury-based chemical that has been used successfully for decades. Public opinion is now questioning its use, but science confirms its safety and suitability for continued use [17]. 5.6.3. Mono-dose preparations The potential for safer injection practices increases with the use of mono-dose, pre-filled vaccine presentations integrated with the injection device. A single dose of vaccine pre-filled into an injection device guarantees the integrity of the vaccine up to the moment of use. Pre-filled, mono-dose injection devices have been available in the US and Europe for almost 20 years. A plastic pouch is now available that holds a single-dose of drug or vaccine linked directly to a hypodermic needle (Uniject® ). This device has been field tested in Bolivia and Indonesia, where health have workers found it easier to use, and where village midwives were able to use it to administer the first dose of Hepatitis B vaccine, raising its coverage [22]. Needle-free devices eliminate both transmission between patients and health workers attributable to accidental needle-stick, as well as the risk of accidents in the community when improperly disposed of. Needle-free devices include: • • • •
jet guns; aerosol nebulizers; dry powder guns; skin patches.
5.6.4. Jet guns Multi-dose injection systems such as jet guns draw vaccine from multi-dose vials of vaccine and can give sequential injections rapidly. They have been available for a number of years and have no risk of accidental needle-stick, with no sharps waste burden and at lowest cost per dose delivered. Earlier multi-dose jet injectors were shown to have an inherent risk of blood-borne transmission [18]. Three possible mechanisms have been proposed to explain this contamination: back-flow from the pressurised skin pocket to the injector’s internal fluid pathway; contamination of the external face of the injector head; splash-back of injected fluid emerging from the injection puncture site. The latest generation of jet injectors are in their final stages of testing but appear to overcome many of the earlier concerns. The Russian BIP-4 injector shows particular promise. Having been developed by the Former USSR in the late 1970s, it has been used extensively in the Ministry of Public Health and the military. Now, the “M” variant has a single-use protector cap that achieves no or virtually no blood con-
C.J. Clements et al. / Vaccine 22 (2004) 2054–2058
tamination. Other designs such as the LectraJetTM allows a change of cartridge containing the vaccine for each dose delivered. 5.6.5. Powder preparations While eliminating the risks associated with accidental needle-stick, liquid needle-free injectors deliver solutions that are less stable than powders and are usually vulnerable to freezing. Liquid injection can also break the skin and cause a wound. For these reasons development and introduction of needle-free injectable solid vaccines is underway. Novel drying technologies, which incorporate antigens in inert, temperature-resistant solids, are set to transform immunisation programmes. Air-drying in the presence of trehalose or its derivatives, produces a powder which is chemically inert, completely heat-stable, unaffected by ambient humidity and whose particle size and rate of dissolution in aqueous liquid can be controlled accurately. A trehalose-based drying and stabilizing technology has already been developed and applied to a number of vaccine antigens [19,20]. As new drying technologies make the development of heat-stable solid vaccines possible, there is an urgent need to develop injection devices capable of delivering them. Parenteral systems are being developed for the delivery of sugar-glass dried vaccines. The most advanced one, named PowderJect® , is designed to deliver powder and could inject particles of sugar-dried vaccine directly into the epidermis. 5.6.6. Oral/nasal preparations Mucosal administration offers obvious advantages in terms of safety as it eliminates the risks of syringe-borne infection (person−to−person, person−to−health worker and environmental). Oral/nasal administration of vaccines are generally more readily accepted than vaccines that require injection. The extensive mucosal surfaces of the digestive, respiratory and reproductive systems are the primary sites for transmission of numerous viral and bacterial diseases (e.g. acute respiratory diseases, sexually transmitted diseases). Immune cells stimulated at one mucosal surface disseminate protection to some other mucosae as well, thus providing the potential for vaccines to be used for a broad spectrum of infectious disease [21]. 5.6.7. Skin patches Vaccines can also be applied directly to intact skin with a skin patch. This new technology has received the name of transcutaneous immunisation [22]. Apart from its beneficial consequences on vaccine safety, its immunological implications are potentially even more profound, as this technique appears to target highly accessible antigen-presenting cells in the skin that can be exploited for a variety of immune outcomes. This technique can be conducted reliably and reproducibly with a variety of antigens to induce potent and functional immune responses.
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6. Safe disposal of equipment Inappropriate disposal of injection equipment, following vaccination or any other form of medical intervention, may place the patient, the health worker and the wider community at risk. It is possible to see contaminated sharps lying on the ground in the vicinity of many hospitals and health centres today. The options for safe disposal include burying in a pit, burning in a specially designed burn box, or burning in an incinerator. Environmental concerns have limited the options for burning, although burning remains an attractive option so long as toxic emissions are limited. Too often, waste is dumped in an uncontrolled way outside a health facility or taken to the municipal site for waste disposal and subject to scavenging and recycling by the very poor. Young children are often the victims of such scavenging, not realising that they place themselves in mortal danger by such acts.
7. Surveillance Monitoring and proper management of adverse events following immunisation (AEFI) are important for the success of the immunisation programme, since such events can influence community acceptance of immunisation. Training of staff in surveillance and management of AEFIs is an essential component of modern immunisation programmes. WHO is advised on issues relating to vaccine safety by a group of external experts who form the Global Advisory Committee on Vaccine Safety. Surveillance reports of concern are brought to the notice of the Committee for consideration. If insufficient data are to hand to answer questions posed by the report, specific research may be commissioned.
8. Public perception No matter how many technologies or training initiatives are introduced to immunisation programmes, if the public perception of the system is that some aspect of vaccines is unsafe, the entire system may be compromised. Although this dynamic is not new, it has reached fresh proportions over the last 5 years. Almost daily there are claims in the media that vaccines are in some way unsafe. For this reason, attention is drawn to the problem in the context of new technologies. Not only does a new device have to be safe, it has to be perceived as safe.
9. Interdependent decisions A number of components of vaccine safety have been identified in the above paragraphs. What may not be self-evident is that a decision to use a particular technology will be inseparable from decisions about strategy, waste disposal and other parts of the system. An example is
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the use of thiomersal-containing multi-dose vaccine vials. WHO continues to promote the use of such vaccines for liquid vaccines such as DTP, hepatitis B vaccine and Hib vaccine. However, if the preservative were to be removed from multi-dose vials, there would need to be a move to mono-dose preparations, a change in the recommendations for storage and discarding, and an increase in the capacity of the cold chain to store approximately 10 times the volume of vials. On the other hand, a move to skin patches would get rid of the need for syringes and needles and would simplify waste disposal. The need for a birth dose of hepatitis B vaccine in highly endemic countries has required the development of a single-dose plastic pouch that can be administered at home by the midwife and disposed of easily.
10. Summary Industry produces vaccines that are extremely safe, but the weakest safety link is their administration. Technologies are welcome that bypasses the ability of man to make bad decisions or to behave incorrectly. The vaccine world is in the middle of a radical re-think about how vaccines might best be administered. The presentation of the vaccine can be altered to fit new technologies such as powder jet guns, or skin patches. Even the conventional needle and syringe have evolved to much safer versions, and are set to continue this evolution. All this means even safer vaccines and their delivery. References [1] Sood DK, Kumar S, Singh S, Sokhey J. Measles vaccination in India and controversies regarding adverse reactions. Vaccine 1995;13:785– 6. [2] Phadke MA, Joshi BN, Warerkar UV, Diwan MP, Panse GA, Sokhey J, et al. Toxic shock syndrome: an unforseen complication following measles vaccination. Indian Pediatr 1991;28:663–5. [3] Vaccine supply and quality. Surveillance of adverse events following immunisation. Wkly Epidemol Rec 1996;71:237–42. [4] Hengster P, Schnapka J, Fille M, Menardi G. Occurrence of suppurative lymphadenitis after a change of BCG vaccine. Arch Dis Child 1992;67:952–5.
[5] Kabra SK, Jain Y, Seth MV. BCG associated adenitis. Lancet 1993;341:970. [6] Noah PK, Smickle MF, Prabhakar P, Pande D, Jonhson B, Ashley D. Outbreak of Bacillus Calmette–Guérin associated lymphadenitis and abscesses in Jamaican children. Pediatr Infect Dis 1990;9:890–3. [7] Technet consultation. Geneva: World Health Organisation [WHO/EPI/LHIS/97.02 (available upon request from the Department of Vaccines and Biologicals, WHO, 1211 Geneva 27, Switzerland)]. [8] State of the world’s vaccines and immunisation. Geneva: World Health Organisation, United Nations Children’s Fund; 1996. p. 159. [9] Kane A, Lloyd J, Zaffran M, Simonsen L, Kane M. Transmission of hepatitis B, hepatitis C and human immunodeficiency viruses through unsafe injections in the developing world: model-based regional estimates. Bull WHO 1999;77:801–7. [10] Hersh BS, Popovici F, Apetrei RC, Zolotusca L, Beldescu N, Calomfirescu A, et al. Acquired immunodeficiency syndrome in Romania. Lancet 1991;14(338):645–9. [11] Darwish MA, Raouf TA, Rushdy P, Constantine NT, Rao MR, Edelman R. Risk factors associated with a high seroprevalence of hepatitis C virus infection in Egyptian blood donors. Am J Trop Med Hyg 1993;49:440–4. [12] Farghaly AG, Barakat RM. Prevalence, impact and risk factors of hepatitis C infection. J Egypt Public Health Assoc 1993;68:63– 79. [13] Safety of injections. WHO-UNICEF policy statement of mass immunisation campaigns. Geneva: World Health Organisation; 1997 [unpublished document WHO/EPI/LHIS/97.04 available upon request from the Department of Vaccines and Biologicals, WHO, 1211 Geneva 27, Switzerland]. [14] Steinglass R, Boyd D, Grabowsky M, Laghari AG, Khan MA, Qavi A, et al. Safety, effectiveness and ease of use of a non-reusable syringe in a developing country. Bull WHO 1995;73:57–63. [15] Nelson CM, Sutanto A, Suradana IG. Use of SoloShot auto-destruct syringes compared with disposable syringes, in a national immunisation campaign in Indonesia. Bull WHO 1999;77:29–33. [16] The use of multi-dose vaccine vials in subsequent immunisation sessions. WHO policy statement. WHO/EPI/LHIS, October 1999. [17] Clements CJ, Ball LK, Ball R, Pratt RD. Thiomersal in vaccines—is removal necessary? Drug Saf 2001;24(8):567–74. [18] Canter J, Mackey K, Good LS, Roberto RR, Chin J, Bond WW, et al. An outbreak of hepatitis B associated with jet injections at a weight reduction clinic. Arch Intern Med 1990;150:1923–7 [Hoffman PN]. [19] Jódar L, Aguado T, Lloyd J, Lambert PH. Revolutionising immunisation. Genetic Engineering News, 15 February 1998. [20] Aguado T, Jódar L, Lloyd J, Lambert PH. Injectable solid vaccines: a role in future immunisation? WHO Drug Inf 1998;12:68–9. [21] Brandtzaeg P. Basic mechanisms of mucosal immunity—a major adaptive defence system. Immunologist 1995;3:89–96. [22] Glenn GM, Rao M, Matyas GR, Alving CR. Skin immunisation made possible by cholera toxin. Nature 1998;391:851.
Technologies that make administration of vaccines safer C. John Clements∗ , Gordon Larsen, Luis Jodar Department of Vaccines and Biologicals, World Health Organization, 1211 Geneva 27, Switzerland
Abstract There is an ever-expanding technology that is aimed at making the administration of vaccines safer. Conventional ways of administering vaccines are being upgraded, modified or replaced by a wide variety of innovations. The paradigm of liquid vaccines, needles and syringes is slow to change, but already developments are ocurring that will change for ever the way vaccines are administered and will improve the safety record of immunization. The oral route of vaccine administration has generally been thought of as safe, but until now only the polio vaccine has been widely used in this way. The conventional method of vaccine administration is by injection. Many ingenious devices have become available that now make injecting safer. Inventors are now looking imaginatively to alternative routes and technologies for delivering vaccines. Vaccines are genreally manufactured to extremely high standards and rarely are shown to be the cause of safety issues. People remain the weakest safety link is vaccine administration. Technologies that bypasses the ability of man to make bad decisions or to behave incorrectly are of tremendous value. The vaccine world is in the middle of a radical re-think about how vaccines might best be administered. The presentation of the vaccine can be altered to fit new technologies such as powder jet guns, or skin patches. Even the conventional needle and syringe have evolved to much safer versions, and are set to continue this evolution. All this means even safer vaccines and their delivery. © 2003 Published by Elsevier Ltd. Keywords: Vaccine; Oral polio vaccine (OPV); Immunisation; Reconstitution; Multi-dose vials; Recapping; Auto-disable syringe; Jet gun; Jet injector; Thiomersal; Trehelose; Oral/nasal administration; Skin patch
1. Introduction There is an ever-expanding technology that is aimed at making the administration of vaccines safer. Fortunately, this technology is not limited to vaccines but is applicable in varying degrees to other health care deliveries, and even to uses outside the human health field. However, the focus of this paper is to provide background information about safe vaccine administration that fits into wider discussions on how to make vaccines as safe as possible. The oral route of vaccine administration has generally been thought of as safe, but until now only the oral polio vaccine (OPV) has been widely used in this way. The conventional method of vaccine administration is by injection. Many ingenious devices have become available that now make injecting safer. Inventors are now looking imaginatively to alternative routes and technologies for delivering vaccines. We are entering a new and safer era of technology that is likely to transform radically the concept of vaccine and drug administration.
∗
Corresponding author. Tel.: +41-22-791-4402; fax: +41-22-791-4193. E-mail address: [email protected] (C.J. Clements).
0264-410X/$ – see front matter © 2003 Published by Elsevier Ltd. doi:10.1016/j.vaccine.2004.01.008
Adverse reactions may be caused by an intrinsic property of the vaccine, by a fault in the vaccine production, by an idiosyncratic response of an individual or by an error in handling or administration. Human error is the hardest to eliminate and is why so many technologies are aimed at bypassing the need for a particular human decision or behaviour. However, most adverse events reported to occur soon after vaccination are not reactions causally related to the vaccination process but are only coincidental events. With a wider possibility of techniques available comes a more complicated set of related choices. The selection of the most appropriate vaccine administration technology, the method of waste disposal, the number of doses of vaccine per vial and a number of other criteria are all inter-related challenges for the health service planner. 2. A wide spectrum of activities A safe vaccine is not simply one that has been manufactured, tested and found to be safe in clinical trials. Important as those aspects are, there are other possibilities for making immunisation safer. These include safe transport to the point of administration, safe administration, safe disposal of the vial and injection equipment, and post-marketing surveil-
C.J. Clements et al. / Vaccine 22 (2004) 2054–2058
lance to detect any unexpected reactions as soon as possible. Finally, even when everything is in place to ensure the safest possible vaccine and its delivery, if the perception of the pubic is that some facet of the system is not safe (no matter what the reality), the entire immunisation programme may be placed in jeopardy.
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constituted vaccine is kept outside the refrigerator. Contamination of reconstituted measles vaccine with Staphylococcus aureus has been documented in a number of countries [1–3]. Reconstituted vaccines should be discarded after 6 h or at the end of the session, whichever is sooner. A preservative such as thiomersal is used in multi-dose liquid vaccines to ensure organisms that accidentally contaminate the vaccine during multiple use are killed off quickly.
3. Safe manufacture Controls imposed on vaccine manufacture ensure a higher standard of production than ever before to the extent that it is extremely unusual to identify production errors as a cause of adverse reactions, even though it is usually the first thought in the public’s mind. The quality of vaccine products is controlled by the National Regulatory Authority (NRA), and batches are not released unless they are passed as having met the requirements of the control authority. Good manufacturing practice (GMP) must be established and maintained. The product must be of high quality and of consistently high quality. Once manufactured, the vaccine must be filled into vials in a way that maintains sterility. 4. Safe transportation—bench to bush A system of technology exists to ensure that the vaccine produced at the bench reaches the bush in the best possible condition. To monitor that correct temperatures have been maintained all the way from the factory, simple monitoring devices have been developed, vaccine vial monitors (VVMs), that are heat-sensitive labels attached to vaccine vials that change colour if temperature limits are violated. Initially, VVMs were used on the labels of oral polio vaccine vials. Now, all vaccines purchased by the United Nations have VVMs on them. Vials that have labels on which the VVM has changed to the wrong colour are discarded. Thus, vials with VVMs can now be used outside the cold chain for community outreach immunisation efforts so long as the VVM does not detect a temperature violation by a change of colour.
5.2. Injection technique training Improper administration of BCG vaccine may lead to BCG lymphadenitis in the lymphatic drainage near the site of the injection. This reaction has mainly been related to a change in vaccine strain without staff being made aware of the need to reconstitute with a different volume of fluid [4–6]. Needles inserted into the buttock to administer vaccines may pass close to the sciatic nerve. Irritant vaccines injected into or close to the nerve have been documented to cause paralysis in some instances. For this reason, careful training is needed to ensure vaccines are injected to the appropriate depth (e.g. intradermal for BCG, subcutaneous for measles vaccine, intramuscular for tetanus toxoid) and appropriate site (outer aspect of the thigh for infants in most cases, and tissue over the deltoid muscle for older children and adults). 5.3. Storage Vaccines must be maintained at the correct cool or cold temperature during transport and storage as well as after reconstitution and during use. Their shelf life (generally 2 years) must not be exceeded. In some health centres and hospitals, potentially dangerous medications may erroneously be kept in the same refrigerator as vaccines. These medications may be packed in vials or ampoules that resemble vaccines or their diluents and may be used by mistake for reconstitution of EPI vaccines. Mistaken use of a muscle relaxant drugs (pavulon or anectine) or insulin were incriminated in several instances, all of which resulted in infant deaths [3].
5. Safe administration
5.4. Recapping needles
5.1. Reconstitution and multiple dose vials
If the vaccinator replaces the cap over the needle after use, there is a high probability that in the process, he will stab himself with the needle tip sooner or later. If the body fluids on the needle are infected with a hepatitis virus, human immunodeficiency virus or other pathogen, the operator may become infected. Accidental needle-stick has become a major public health problem. Studies in Western Europe and the USA showed that as much as 87% of health workers under-report needle-stick injuries [7]. WHO recommends that needle recapping should not be undertaken but that the syringe and needle should be disposed of immediately after use into a “sharps box” or other secure container.
While freeze drying of vaccines makes for an excellent method of vaccine manufacture and long-term storage, it also provides an opportunity for human error at the point when it is reconstituted back into a liquid. For example, unsterile procedures during reconstitution or inadequate storage and use of reconstituted vaccine over a number of immunisation sessions are likely to result in contamination of the vaccine. BCG vaccine has no preservative at all and measles vaccines contain limited amounts of antibiotics. Therefore, rapid multiplication of pathogens can take place, especially when re-
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5.5. Equipment Syringes and multi-dose vials are the main elements of the delivery system for immunisation services in developing countries today, accounting for 80% of the vaccines administered globally. Of the 12 billion syringes sold each year for medical injections, only 5% (around 1 billion) are used for vaccines. Yet the number of antigens routinely administered is increasing rapidly and it is anticipated that the number of injections will increase further [8]. Worryingly, a substantial number of the injections administered world-wide are not administered in a way that can guarantee sterility. A WHO-sponsored review [3] of unsafe injection practices in the developing world showed that at least 50% of all injections were unsafe in Asia, sub-Saharan Africa and the former Soviet Republic, exposing patients to the risk of infection from hepatitis, HIV or other blood-borne pathogens [9–11]. Syringes and needles are widely re-used in developing countries because of scarcity, re-sale value and a cultural resistance to waste. More than 30% of immunisation injections may be unsafe, primarily due to re-use [12]. In developing countries, the conditions of work are arguably more difficult and extreme. For example, over half of the injections for immunisation are provided with sterilizeable syringes and needles, items that must be handled and cleaned individually before sterilisation. 5.6. Safe technologies While current vaccine administration techniques are well tested, their simplicity and safety profiles can be much improved. Designing systems that are simpler and less prone to adverse events, regardless of the human factor, are therefore very attractive. The current biotechnological revolution, together with increased knowledge about immune responses, are promoting the construction of new delivery systems and technologies that may revolutionise immunisation programmes beyond recognition. 5.6.1. Auto-disable syringe The preferred syringe for mass immunisation campaigns is now the auto-disable (A–D) syringe [13]. This syringe has been tested both in the laboratory and field [14], and has been shown to be easier to use and preferred by the health worker. Overall, the A–D syringe contributes to decreased blood-borne pathogen transmission between patients by preventing re-use and re-sale, both common practices in developing countries. In a field trial in Indonesia, the SoloShot® A–D syringe delivered more precise and consistent doses and 15% more doses per vial than disposable syringes [15]. 5.6.2. Preservatives Multi-dose vials have been the standard presentation of the majority of vaccines used in developing countries.
WHO’s current policy [16] allows certain multi-dose vials to be used over a period of a month to control wastage and ensure the administration of vaccine when only a few children attend each vaccination session. Multi-dose vials of liquid vaccine need the presence of a preservative in them to ensure sterility once the vial has been opened. The commonest preservative is thiomersal, a mercury-based chemical that has been used successfully for decades. Public opinion is now questioning its use, but science confirms its safety and suitability for continued use [17]. 5.6.3. Mono-dose preparations The potential for safer injection practices increases with the use of mono-dose, pre-filled vaccine presentations integrated with the injection device. A single dose of vaccine pre-filled into an injection device guarantees the integrity of the vaccine up to the moment of use. Pre-filled, mono-dose injection devices have been available in the US and Europe for almost 20 years. A plastic pouch is now available that holds a single-dose of drug or vaccine linked directly to a hypodermic needle (Uniject® ). This device has been field tested in Bolivia and Indonesia, where health have workers found it easier to use, and where village midwives were able to use it to administer the first dose of Hepatitis B vaccine, raising its coverage [22]. Needle-free devices eliminate both transmission between patients and health workers attributable to accidental needle-stick, as well as the risk of accidents in the community when improperly disposed of. Needle-free devices include: • • • •
jet guns; aerosol nebulizers; dry powder guns; skin patches.
5.6.4. Jet guns Multi-dose injection systems such as jet guns draw vaccine from multi-dose vials of vaccine and can give sequential injections rapidly. They have been available for a number of years and have no risk of accidental needle-stick, with no sharps waste burden and at lowest cost per dose delivered. Earlier multi-dose jet injectors were shown to have an inherent risk of blood-borne transmission [18]. Three possible mechanisms have been proposed to explain this contamination: back-flow from the pressurised skin pocket to the injector’s internal fluid pathway; contamination of the external face of the injector head; splash-back of injected fluid emerging from the injection puncture site. The latest generation of jet injectors are in their final stages of testing but appear to overcome many of the earlier concerns. The Russian BIP-4 injector shows particular promise. Having been developed by the Former USSR in the late 1970s, it has been used extensively in the Ministry of Public Health and the military. Now, the “M” variant has a single-use protector cap that achieves no or virtually no blood con-
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tamination. Other designs such as the LectraJetTM allows a change of cartridge containing the vaccine for each dose delivered. 5.6.5. Powder preparations While eliminating the risks associated with accidental needle-stick, liquid needle-free injectors deliver solutions that are less stable than powders and are usually vulnerable to freezing. Liquid injection can also break the skin and cause a wound. For these reasons development and introduction of needle-free injectable solid vaccines is underway. Novel drying technologies, which incorporate antigens in inert, temperature-resistant solids, are set to transform immunisation programmes. Air-drying in the presence of trehalose or its derivatives, produces a powder which is chemically inert, completely heat-stable, unaffected by ambient humidity and whose particle size and rate of dissolution in aqueous liquid can be controlled accurately. A trehalose-based drying and stabilizing technology has already been developed and applied to a number of vaccine antigens [19,20]. As new drying technologies make the development of heat-stable solid vaccines possible, there is an urgent need to develop injection devices capable of delivering them. Parenteral systems are being developed for the delivery of sugar-glass dried vaccines. The most advanced one, named PowderJect® , is designed to deliver powder and could inject particles of sugar-dried vaccine directly into the epidermis. 5.6.6. Oral/nasal preparations Mucosal administration offers obvious advantages in terms of safety as it eliminates the risks of syringe-borne infection (person−to−person, person−to−health worker and environmental). Oral/nasal administration of vaccines are generally more readily accepted than vaccines that require injection. The extensive mucosal surfaces of the digestive, respiratory and reproductive systems are the primary sites for transmission of numerous viral and bacterial diseases (e.g. acute respiratory diseases, sexually transmitted diseases). Immune cells stimulated at one mucosal surface disseminate protection to some other mucosae as well, thus providing the potential for vaccines to be used for a broad spectrum of infectious disease [21]. 5.6.7. Skin patches Vaccines can also be applied directly to intact skin with a skin patch. This new technology has received the name of transcutaneous immunisation [22]. Apart from its beneficial consequences on vaccine safety, its immunological implications are potentially even more profound, as this technique appears to target highly accessible antigen-presenting cells in the skin that can be exploited for a variety of immune outcomes. This technique can be conducted reliably and reproducibly with a variety of antigens to induce potent and functional immune responses.
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6. Safe disposal of equipment Inappropriate disposal of injection equipment, following vaccination or any other form of medical intervention, may place the patient, the health worker and the wider community at risk. It is possible to see contaminated sharps lying on the ground in the vicinity of many hospitals and health centres today. The options for safe disposal include burying in a pit, burning in a specially designed burn box, or burning in an incinerator. Environmental concerns have limited the options for burning, although burning remains an attractive option so long as toxic emissions are limited. Too often, waste is dumped in an uncontrolled way outside a health facility or taken to the municipal site for waste disposal and subject to scavenging and recycling by the very poor. Young children are often the victims of such scavenging, not realising that they place themselves in mortal danger by such acts.
7. Surveillance Monitoring and proper management of adverse events following immunisation (AEFI) are important for the success of the immunisation programme, since such events can influence community acceptance of immunisation. Training of staff in surveillance and management of AEFIs is an essential component of modern immunisation programmes. WHO is advised on issues relating to vaccine safety by a group of external experts who form the Global Advisory Committee on Vaccine Safety. Surveillance reports of concern are brought to the notice of the Committee for consideration. If insufficient data are to hand to answer questions posed by the report, specific research may be commissioned.
8. Public perception No matter how many technologies or training initiatives are introduced to immunisation programmes, if the public perception of the system is that some aspect of vaccines is unsafe, the entire system may be compromised. Although this dynamic is not new, it has reached fresh proportions over the last 5 years. Almost daily there are claims in the media that vaccines are in some way unsafe. For this reason, attention is drawn to the problem in the context of new technologies. Not only does a new device have to be safe, it has to be perceived as safe.
9. Interdependent decisions A number of components of vaccine safety have been identified in the above paragraphs. What may not be self-evident is that a decision to use a particular technology will be inseparable from decisions about strategy, waste disposal and other parts of the system. An example is
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the use of thiomersal-containing multi-dose vaccine vials. WHO continues to promote the use of such vaccines for liquid vaccines such as DTP, hepatitis B vaccine and Hib vaccine. However, if the preservative were to be removed from multi-dose vials, there would need to be a move to mono-dose preparations, a change in the recommendations for storage and discarding, and an increase in the capacity of the cold chain to store approximately 10 times the volume of vials. On the other hand, a move to skin patches would get rid of the need for syringes and needles and would simplify waste disposal. The need for a birth dose of hepatitis B vaccine in highly endemic countries has required the development of a single-dose plastic pouch that can be administered at home by the midwife and disposed of easily.
10. Summary Industry produces vaccines that are extremely safe, but the weakest safety link is their administration. Technologies are welcome that bypasses the ability of man to make bad decisions or to behave incorrectly. The vaccine world is in the middle of a radical re-think about how vaccines might best be administered. The presentation of the vaccine can be altered to fit new technologies such as powder jet guns, or skin patches. Even the conventional needle and syringe have evolved to much safer versions, and are set to continue this evolution. All this means even safer vaccines and their delivery. References [1] Sood DK, Kumar S, Singh S, Sokhey J. Measles vaccination in India and controversies regarding adverse reactions. Vaccine 1995;13:785– 6. [2] Phadke MA, Joshi BN, Warerkar UV, Diwan MP, Panse GA, Sokhey J, et al. Toxic shock syndrome: an unforseen complication following measles vaccination. Indian Pediatr 1991;28:663–5. [3] Vaccine supply and quality. Surveillance of adverse events following immunisation. Wkly Epidemol Rec 1996;71:237–42. [4] Hengster P, Schnapka J, Fille M, Menardi G. Occurrence of suppurative lymphadenitis after a change of BCG vaccine. Arch Dis Child 1992;67:952–5.
[5] Kabra SK, Jain Y, Seth MV. BCG associated adenitis. Lancet 1993;341:970. [6] Noah PK, Smickle MF, Prabhakar P, Pande D, Jonhson B, Ashley D. Outbreak of Bacillus Calmette–Guérin associated lymphadenitis and abscesses in Jamaican children. Pediatr Infect Dis 1990;9:890–3. [7] Technet consultation. Geneva: World Health Organisation [WHO/EPI/LHIS/97.02 (available upon request from the Department of Vaccines and Biologicals, WHO, 1211 Geneva 27, Switzerland)]. [8] State of the world’s vaccines and immunisation. Geneva: World Health Organisation, United Nations Children’s Fund; 1996. p. 159. [9] Kane A, Lloyd J, Zaffran M, Simonsen L, Kane M. Transmission of hepatitis B, hepatitis C and human immunodeficiency viruses through unsafe injections in the developing world: model-based regional estimates. Bull WHO 1999;77:801–7. [10] Hersh BS, Popovici F, Apetrei RC, Zolotusca L, Beldescu N, Calomfirescu A, et al. Acquired immunodeficiency syndrome in Romania. Lancet 1991;14(338):645–9. [11] Darwish MA, Raouf TA, Rushdy P, Constantine NT, Rao MR, Edelman R. Risk factors associated with a high seroprevalence of hepatitis C virus infection in Egyptian blood donors. Am J Trop Med Hyg 1993;49:440–4. [12] Farghaly AG, Barakat RM. Prevalence, impact and risk factors of hepatitis C infection. J Egypt Public Health Assoc 1993;68:63– 79. [13] Safety of injections. WHO-UNICEF policy statement of mass immunisation campaigns. Geneva: World Health Organisation; 1997 [unpublished document WHO/EPI/LHIS/97.04 available upon request from the Department of Vaccines and Biologicals, WHO, 1211 Geneva 27, Switzerland]. [14] Steinglass R, Boyd D, Grabowsky M, Laghari AG, Khan MA, Qavi A, et al. Safety, effectiveness and ease of use of a non-reusable syringe in a developing country. Bull WHO 1995;73:57–63. [15] Nelson CM, Sutanto A, Suradana IG. Use of SoloShot auto-destruct syringes compared with disposable syringes, in a national immunisation campaign in Indonesia. Bull WHO 1999;77:29–33. [16] The use of multi-dose vaccine vials in subsequent immunisation sessions. WHO policy statement. WHO/EPI/LHIS, October 1999. [17] Clements CJ, Ball LK, Ball R, Pratt RD. Thiomersal in vaccines—is removal necessary? Drug Saf 2001;24(8):567–74. [18] Canter J, Mackey K, Good LS, Roberto RR, Chin J, Bond WW, et al. An outbreak of hepatitis B associated with jet injections at a weight reduction clinic. Arch Intern Med 1990;150:1923–7 [Hoffman PN]. [19] Jódar L, Aguado T, Lloyd J, Lambert PH. Revolutionising immunisation. Genetic Engineering News, 15 February 1998. [20] Aguado T, Jódar L, Lloyd J, Lambert PH. Injectable solid vaccines: a role in future immunisation? WHO Drug Inf 1998;12:68–9. [21] Brandtzaeg P. Basic mechanisms of mucosal immunity—a major adaptive defence system. Immunologist 1995;3:89–96. [22] Glenn GM, Rao M, Matyas GR, Alving CR. Skin immunisation made possible by cholera toxin. Nature 1998;391:851.