Following the 1996 CDC/WHO conference, the WHO actively engaged in meetings and conducted further evaluations on the safety of multi-use nozzle jet injectors (MUNJI). During this time, WHO continued to discourage the use of MUNJI’s under any circumstance. The timeline below shows the reports, conferences, and studies in which the WHO investigated MUNJI devices.
1986 WHO Report – Selection of Injection Equipment for the Expanded Program on Immunization
In October of 1986, the World Health Organization (WHO) changed its policy on the use of jet injectors. The policy change was the direct result of a hepatitis outbreak due to the use of a MUNJI device. WHO’s highly publicized statement said,
Until further studies clarify the risks of disease transmission associated with jet injectors, general caution in their use is recommended (WHO, 1986).
Their use should be restricted to special circumstances where the use of needles and syringes is not feasible because of the large numbers of persons to be immunized within a short period of time (WHO/UNICEF, 1987).
1995 WHO Requests the Help of Dr. Peter Hoffman
In 1995, the World Health Organization requested the help of Dr. Peter Hoffman of United Kingdom’s Public Health Laboratory Service. Dr. Hoffman was brought on to create a model to detect whether low, but infectious, volumes of blood were being transferred via various jet injectors (Fields, 1996). In a personal interview with this author in 2013, Hoffman stated,
I was part of a team studying a small range of jet injectors, trying to establish general truths rather than study specific injectors. I was observing whether there were any problems of blood transmission between sequential recipients of injections rather than trying to fix any specific problem (Hoffman, 2013).
This would mark WHO’s first investigation into the safety of multi-use nozzle jet injectors.
1995 CDC & WHO Meeting – Review the Safety of Jet Injectors
CDC met with WHO in London in 1995 to rewrite the safety standards for all jet injectors. Also present for the meeting were Dr. Hoffman and a representative from PATH. CDC and WHO both agreed the safety standard for jet injectors should be raised to a “zero tolerance” level (Fields, 1996). This meeting subsequently led to a CDC/WHO conference on jet injector safety in 1996.
1996 CDC & WHO Conference – Jet Injectors for Immunization, Current Practice and Safety, Improving Designs for the Future
CDC and WHO invited various health agencies, manufacturers, and consumers to discuss the safety of jet injectors. The goal of this meeting was for all involved parties to discuss ways in achieving a zero-risk jet injector.
During the conference Dr. Hoffman gave a presentation titled, Animal-model Assessment of Jet Injector Safety, in which he described a laboratory investigation for testing cross-contamination from jet injectors (Fields, 1996).
1996 WHO Discourages Use of Jet Injectors
WHO unofficially reversed its 1994 policy and advised against the use of jet injectors under any circumstances. The change in policy resulted from fears of spreading blood-borne pathogens, such as Hepatitis B, Hepatitis C, and HIV with Ped-O-Jet injectors during a massive meningitis outbreak in Nigeria in 1996 (Mohammed et al., 2000). However, this policy change was not widely publicized until 1998 (Fields, 1996). Article – Nigeria Forced to Use Ped-O-Jet Injectors in 1996 Despite Fears of Spreading Hepatitis and AIDS
1997 Hoffman’s Initial Investigation of Med-E-Jet
Hoffman’s initial laboratory investigation in 1997 tested the volume of contamination after a Med-E-Jet injector administered an injection into calves. Working with Dr. Hoffman and the WHO was Dr. RA Abuknesha from King’s College, London. Dr. Abuknesha developed an enzyme-linked immunosorbent assay (ELISA) to detect Human Serum Albumin, which was used as a marker to detect blood within the ejectates from the jet injectors (FDA, 1999; Friede, 2003). Results from this investigation showed systemic contamination of the ejectate (WHO, 1997). At the time, Hoffman and WHO concluded,
the path of contamination may have been reflux within the jet stream. This could possibly have occurred at the end of the shot when the liquid pressure at the nozzle of the injector dies to a level lower than that of the liquid column within the skin and subcutaneous tissue of the animal…The implication of these results is that, for jet injection to be safe, the entire fluid path must be changed between injections (WHO, 1997).
While it is true that the enzyme-linked immunosorbent assay (ELISA) is used to detect Human Serum Albumin (HSA) and HSA is found within blood, saliva, and skin cells, it is also true that the researchers took extensive precautionary measures to avoid any false positives within the data.
1997 WHO & CDC Conference – Steering Group on the Development of Jet Injection For Immunization
Hoffman’s initial findings of the Med-E-Jet were presented at the conference. Members were also informed that contamination was believed to be due from an undesirable phenomenon called retrodgrade flow. The consensus at the conference was other jet injectors, such as the Ped-O-Jet, should be evaluated to see if they succumb to retrograde flow as well. Further laboratory and field trials were planned. Also, members agreed in pursuing development of zero-risk devices, such as disposable-cartridge jet injectors (WHO, 1997).
1998 (March 25) WHO Conference – Technet Consultation
At a conference in Copenhagen, WHO presented preliminary findings of it’s laboratory investigation by Hoffman and colleagues. “The results so far obtained with three injector models show that there is an unacceptable level of downstream contamination, irrespective of whether the nozzle is discarded after each injection” (WHO, 1998a). Preliminary analysis of the Ped-O-Jet found 29 percent of the samples (29 out of 100) contained more than 10 picoliters of blood. The Medivax, protector cap needle-free injector, found a 31 percent contamination rate (11 out of 35 samples). The Med-E-Jet found a 72.7 percent contamination rate (16 out of 22 samples). The researchers further speculated contamination was the result of retrograde flow which “probably [occurs] at the end of the injection when the internal pressure of the injector drops” (WHO, 1998a).
Based upon these findings WHO stated,
Multidose, needle-free injectors with a reusable fluid path should only be used for immunization if they pass standard WHO safety tests. On this basis the latest evidence suggests that none of the models that have been tested [i.e., Ped-O-Jet, Med-E-Jet & Medivax] in the laboratory can be used for immunization” (WHO, 1998a).
This is worth repeating. The most widely used jet injector in the world, the Ped-O-Jet, did not pass WHO’s safety test and therefore cannot be used for administering immunizations. This would also mean the Ped-O-Jet should never have been used.
During this conference WHO officially discouraged the use of jet injectors under any circumstance and recommended the use of needles and syringes. “Until safe needle-free injectors are identified through independent safety testing, only needles and syringes should be used for immunization” (WHO, 1998a).
1998 (October) WHO Report – Safety of Injections
For the first time, WHO publishes warnings against the use of multi-use nozzle jet injectors. “Needle-free injectors designed for use with multi-dose vials and with a multiple-use fluid path should not be used for immunization. These injectors have an inherent risk of bloodborne disease transmission,” stated the report (emphasis added) (WHO, 1998b).
1998 (October) Ped-O-Jet Field Trial in Brazil
In October of 1998, WHO conducted a simulated field trial with Ped-O-Jet injectors to assess the degree of blood transmission via multi-use nozzle jet injectors. The investigation was a collaborative effort between WHO, the Brazilian Ministry of Health and Dr. Hoffman. The field trial administered saline injections to patients infected with Hepatitis B and Hepatitis C in the Brazilian cities of São Paulo and Belém (Hoffman et al., 2000). The researchers replicated de Souza Brito’s 1992 study but used a new ELISA method for detecting the presence of occult blood (Hoffman et al., unpublished).
In the first test, volunteers received a saline injection with a Ped-O-Jet injector, immediately followed by three subsequent shots into three test tubes. Covering the top of each test tube was a plastic film which was “used to replicate the effect of skin as a barrier to contamination transfer.” The ejectates within these three test tubes were assayed. These subsequent shots represented what the following three persons standing in the vaccination line would have received. The researchers were assessing if blood would be cross-contaminated to subsequent vaccinees when the nozzle of the jet injector was not swabbed (Hoffman et al., unpublished; Hoffman et al., 2000).
Positive samples were defined as any ejectate containing 10 picoliters of blood or more. Results for the first test, when the nozzle was not swabbed, found 13 out of 117 (11.1%) of the samples collected after the first inoculation had greater than 10 picoliters of blood. Results of the second “shot” found 4 out of 117 (3.4%) of the samples were positive and the third “shot” found no contamination (Hoffman et al., unpublished; Hoffman et al., 2000).
In the second test, immediately following an injection the nozzle of the Ped-O-Jet was swabbed with a piece of cotton soaked in ethyl alcohol. Three subsequent shots were fired into three test tubes and the ejectates were assayed.
Results of the second test, when the nozzle was swabbed, found 9 out of 117 (7.7%) of the samples collected after the first inoculation had greater than 10 picoliters of blood. Results of the second “shot” found 3 out of 117 (2.7%) of the samples were positive and the third “shot” found no contamination (Hoffman et al., unpublished; Hoffman et al., 2000).
These results signify several findings: 1) Swabbing the nozzle of the Ped-O-Jet did not eliminate but only slightly reduced the degree of contamination. This finding indicates contamination was present inside the injector’s internal fluid pathway, beyond the reach of swabbing the nozzle. This undesirable phenomenon is known as retrograde flow. The researchers stated, “This trial has confirmed previous laboratory modeling carried out by the same investigating team in London, showing that significant blood contamination can be transferred by jet injectors” (Hoffman et al., unpublished).
2) Once the Ped-O-Jet became contaminated it remained contaminated up to the following two subsequent injections.
3) Cross-contamination occurred despite the presence of visible bleeding at the injection site. “Blood contamination did not seem to correlate with the rapidity or profundity of bleeding at the injection site, nor with individual injectors used,” said the researchers.
In 29 samples more than 10 picoliters of blood was cross-contaminated via the Ped-O-Jet. In 14 out of the 29 positive samples, there was no visible bleeding at the injection site. Out of these 14 instances where no visible bleeding was observed, 11 samples were first shots and 3 samples were second shots (Hoffman et al., unpublished). These findings indicate that despite the lack of any visible bleeding at the injection site the Ped-O-Jet became so grossly contaminated that transmission of a relevant volume of blood occurred into the subsequent two injections.
Dr. Martin Friede, from WHO’s Initiative for Vaccine Research, described the significance of Hoffman’s findings at a 2005 FDA panel discussion on jet injector safety. Dr. Friede stated,
The devices that we have seen without a protection cap, we have data from the calves and the data from the Hoffman study in Brazil to show that frequent contamination of the ejected did take place. And that contamination was clearly of a level of blood that we are convinced can carry disease. So the devices which do not have a protection cap which are to be used for giving intramuscular injection we are convinced that these carry a significant risk (emphasis added) (FDA, 2005).
The field trial took cautionary measures to avoid false positives from the use of Human Serum Albumin (HSA) as a marker for detecting blood, since HSA is also found within saliva and skin cells. “Throughout this work, great care was exercised to exclude extraneous contamination with human serum albumin (HSA),” said Hoffman. “Operators wore face masks and gloves whilst handling unsealed specimen vials and during sample collection.” Moreover, measures were in place for assessing any pre- and post-injection HSA contamination which would have altered the data (Hoffman et al., unpublished).
2001 Hoffman et al. Publish Findings on Jet Injector Safety
Hoffman and colleagues finally published the results of their laboratory investigation in 2001. Four different types of jet injectors were analyzed: Ped-O-Jet/Am-O-Jet, Medivax, Jet2000, and Med-E-Jet. The Am-O-Jet was an identical design to the Ped-O-Jet device (American Jet Injector; Weniger & Papania, 2008). Two of the jet injectors–Medivax and Jet2000–were prototypes.
“All injectors tested transmitted significant (over 10 pl) volumes of blood; the volumes and frequency of contamination varied with injector” (Hoffman et al., 2001). These findings were astonishing. If 10 picoliters is a sufficient amount of blood for transmitting blood-borne pathogens then this value (i.e., 10 pl) can be used as a threshold level in determining a contamination rate amongst the sampling of jet injectors. Results found the Ped-O-Jet had a 34.2 percent contamination rate. The Med-E-Jet had a 97.4 percent contamination rate. The two prototype injectors were also found to transmit relevant amounts of blood. The Medivax had a 95.8 percent contamination rate. The Jet2000, which had a single-use plastic protector cap that protected the reusable nozzle, had a 42.0 percent contamination rate.
In an extended sampling, the Med-E-Jet nozzle was wiped with alcohol between subsequent injections. Results found a lower contamination rate than in the initial series where the nozzle head was not wiped. In other words, there was still contamination even after the nozzle was swabbed. These results demonstrate when the nozzle is swabbed only superficial contamination is removed and sterilization of the internal fluid pathways is neglected.
The results also found a significant number of samplings consisted of greater than 50 picoliters of blood. The Ped-O-Jet had a 16.6 percent contamination rate at this higher threshold. The Med-E-Jet had a 85 percent contamination rate. The Medivax had a 85.4 percent contamination rate. The Jet2000 had a 20.1 percent contamination rate (Hoffman et al., 2001).
Hoffman’s laboratory investigations took cautionary measures so as to not let HSA alter the data of the ELISA. “Stringently applied protocols” were utilized which included the need for “an extremely clean environment.” Injection sites of calves were cleansed twice with methanol. Vaccinators rinsed their hands with ethanol before handling a jet injector and bulk reagents (Hoffman et al., 2001).
Another limitation of the ELISA method is the necessity for diluting a sample that has been frozen. Daya Ranamukha-arachchi, a molecular biologist at the Office of Science at the Center for Devices and Radiological Health within the FDA, stated, “Under cold storage conditions serum albumin can bind to collection tubes…so you have to go through a series of dilutions in order to get within the dynamic range of detection” (FDA, 2005). Through this method some of the quantity of contamination can be lost.
Dr. Hoffman estimated a 30 to 50 percent loss of blood within the samples of his study. “Freezing solutions with low concentrations of proteins causes loss of detectable protein, probably due to the absorption of surfaces. We estimate…losses of analyte of around 30 – 50 %, and so our results are underestimates of blood contamination” (Hoffman et al., 2001).
Hoffman and colleagues (2001) concluded cross-contamination occurred because the newly deposited jet stream in the skin had developed a pressure greater than the declining pressure in the jet injector causing a backwards flow. This backwards or rather retrograde flow of fluid—and now blood and bodily fluids—shoots back into the internal fluid pathway of the jet injector.
2004 (March 30) WHO & CDC Meeting – Consultation on MUNJI Safety Evaluation
WHO and CDC hosted a subsequent meeting on jet injector safety at WHO Headquarters in Geneva, Switzerland. The goal of this meeting was to establish criteria for a new generation of jet injector devices. Attendees of the meeting came to a consensus on several points: 1) A fraction of a picoliter can transmit infection, thus making the 10 picoliter threshold irrelevant (FDA, 2005). 2) No level of risk is acceptable with the use of MUNJIs. Therefore jet injectors need to show they pose zero-risk to vaccinees (Weniger, 2005). 3) Previous animal models are irrelevant in assessing the risk for humans (Weniger, 2005). Future jet injector safety trials should use human HBsAg carriers and use the most sensitive PCR assays for contamination within ejectates (Weniger, Jones & Chen). The PCR assay is a more sensitive assay than the ELISA, a difference of ~3 picoliters and ~13 picoliters, respectively.
2005 (Aug 9) FDA Hearing – MUNJI Safety
WHO partook in a panel discussion on jet injectors at the FDA. Dr. Martin Friede, of the WHO, gave an in depth discussion on the risks of jet injectors and stated WHO’s ultimate position on MUNJIs. “The determination of the safety of MUNJIs is the responsibility of national regulatory agencies. WHO will not determine the safety. This is the responsibility of the national regulatory agencies,” said Friede (FDA, 2005).
WHO was willing to investigate and report its findings on MUNJI devices and even openly discourage against their use. However, ultimately the WHO did not want to get involved within any national regulatory determination.
The WHO was always quick to restrict and warn against the use of multi-use nozzle jet injectors. The agency was actively involved in investigating MUNJIs for many years before respectfully bowing-out in 2005. It is my belief that a more prominent position by the WHO would have been to conduct epidemiological studies evaluating the risks of MUNJIs used in mass vaccination campaigns.
For an agency, such as the WHO, to publish numerous studies throughout the 1960s and 1970s on how MUNJIs were a better way for administering immunizations and to subsequently investigate the risks of cross-contamination by MUNJIs throughout the 1990s then it would be logical and moral for the WHO to investigate how many people became infected with a blood-borne pathogen after receiving immunizations with MUNJI devices.
- (American Jet Injector) American Jet Injector, Lansdale, PA; 19446-4520, USA; firstname.lastname@example.org (the Am-O-Jet™ is an exact design of the out-of-patent Ped-O-Jet® device).
- (FDA, 1999) Food and Drug Administration. General Hospital & Personal Use Devices panel: open session. Department of Health and Human Services Meeting. Rockville, MD. 2 August 1999.
- (FDA, 2005) FDA. General Hospital and Personal Use Devices Panel of the Medical Devices Advisory Committee. August 9, 2005. 35th Conference. Washington, D.C.
- (Fields, 1996) Fields R. Participation in Meeting: Jet injectors for immunization; current practice and safety; improving designs for the future. WHO/CDC Meeting. Atlanta, GA. 2-3 October, 1996. Available at: http://pdf.usaid.gov/pdf_docs/PNABZ997.pdf.
- (Friede, 2003) Friede M. Safety Evaluation of Re-designed Multi-Use-Nozzle Jet Injectors (presentation). Innovative Administration Systems for Vaccines Conference, Rockville, Maryland. 18-19 December 2003.
- (Hoffman et al., 2000) Hoffman PN, Abuknesha RA, Andrews NJ, Brito de Souza G, Carrasco P, Weckx LY, Moia LJMP, Silva AEB, Lloyd J. Avaliação de segurança em injetores à pressão para vacinação no Brasil. Centro de Vigilância Epidemiológica (CVE) Boletim Informativo. July 2000;15(57):3-5.
- (Hoffman et al., 2001) Hoffman PN, Abuknesha RA, Andrews NJ, Samuel D, Lloyd JS. A model to assess the infection potential of jet injectors used in mass immunization. Vaccine 19 (2001): 4020-4027.
- (Hoffman et al., unpublished) Hoffman PN, Abuknesha RA, Andrews NJ, Brito GS, Carrasco P, Weckx LY, Moia LJMP, Silva AEB, Lloyd J. A field trial of jet injector safety in Brazil. (unpublished).
- (Mohammed et al., 2000) Mohammed I, Abdussalam N, Alkali AS, Garbati MA, Ajayi-Obe EK, Audu KA, Usman A, Abdullahi S. A Severe Epidemic of Meningococcal Meningitis in Nigeria, 1996. Royal Society of Tropical Medicine and Hygiene, 2000 (94): 265-270.
- (Weniger, 2005) Weniger B. Safety of Multi-use-nozzle Jet Injectors (MUNJIs) for Bloodborne Pathogen Cross-contamination [draft]. Conference Notes. 7 August 2005.
- (Weniger, Jones & Chen) Weniger BC, Jones TS, & Chen RT. The Unintended Consequences of Vaccine Delivery Devices Used to Eradicate Smallpox: Lessons for Evaluating Future Vaccination Methods.
- (Weniger & Papania, 2008) Weniger BG, Papania MJ. Alternative Vaccine Delivery Methods [Chapter 61]. In: Plotkin SA, Orenstein WA, Offit PA, eds. Vaccines, 5th ed. Philadelphia, PA: Saunders (Elsevier); 2008;1357-1392.
- (WHO, 1986) WHO/EPI. WHO/UNICEF Joint Guidelines. Selection of Injection Equipment for the Expanded Programme on Immunization. 1986. WHO/UNICEF/EPI.T5/ 86.27597.
- (WHO/UNICEF, 1987) WHO/UNICEF. Expanded Program on Immunization-Joint WHO/UNICEF Statement on Immunization and AIDS. 1987. pp 18-19.
- (WHO, 1997) World Health Organization. Steering group on the development of jet injection for immunization. May 14, 1997. [draft]
- (WHO, 1998a) World Health Organization. Technet Consultation. Expanded Programme on Immunization. Conference 16-20 March 1998. Copenhagen. WHO/EPI/LHIS/98.05.
- (WHO, 1998b) World Health Organization. Safety of injections in immunization programmes: WHO recommended policy. Geneva: World Health Organization, Global Programme on Vaccines and Immunizations, document WHO/EPI/LHIS/96.05, Rev. 1, Oct 1998;1-11.