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Is it time for a new yellow fever vaccine?
Vaccine 28 (2010) 8073–8076
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Review
Is it time for a new yellow fever vaccine? Edward B. Hayes ∗ Barcelona Centre for International Health Research, Rosselo 132, 08036 Barcelona, Spain
a r t i c l e
i n f o
Article history: Received 17 June 2010 Received in revised form 7 September 2010 Accepted 7 October 2010 Available online 3 November 2010 Keywords: Yellow fever Yellow fever vaccine Global health Traveler’s health Flavivirus vaccine
a b s t r a c t An inexpensive live attenuated vaccine (the 17D vaccine) against yellow fever has been effectively used to prevent yellow fever for more than 70 years. Interest in developing new inactivated vaccines has been spurred by recognition of rare but serious, sometimes fatal adverse events following live virus vaccination. A safer inactivated yellow fever vaccine could be useful for vaccinating people at higher risk of adverse events from the live vaccine, but could also have broader global health utility by lowering the riskbenefit threshold for assuring high levels of yellow fever vaccine coverage. If ongoing trials demonstrate favorable immunogenicity and safety compared to the current vaccine, the practical global health utility of an inactivated vaccine is likely to be determined mostly by cost. © 2010 Elsevier Ltd. All rights reserved.
Contents Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8075 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8075
Yellow fever is one of the great infectious scourges of humankind, ranking in historical impact with plague and smallpox. It is a fearsome disease and, unlike smallpox, has never been fully controlled. Yellow fever virus is endemically transmitted in forests and savannas of South America and Africa, periodically emerging from enzootic cycles to cause epidemics of hemorrhagic fever with case fatality rates ranging from 20% to 50% [1]. Thousands of cases of yellow fever are reported to WHO each year from tropical areas of Africa and South America, and rare sporadic cases occur among travelers to endemic areas. The 17D live attenuated yellow fever virus vaccine was developed in the 1930s through work that was recognized with a Nobel Prize awarded to Max Theiler in 1951. The vaccine was used in field trials in 1937, and over the intervening 73 years has been given to more than 500 million people and considered one of the most effective and safe vaccines ever developed [2]. A single dose of 17D yellow fever vaccine confers long-term immunity, and costs less than one U.S. dollar for use in endemic countries [1]. All that seems hard to beat, so do we need another yellow fever vaccine? In 2001 three articles first described a new type of serious adverse event after yellow fever vaccination [3–5]. The vaccine
∗ Tel.: +34 93 227 1852. E-mail address: [email protected] 0264-410X/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2010.10.015
recipients developed an illness that closely resembled wild type yellow fever and had a similarly high fatality rate. This multiorgan system failure after vaccination was later named yellow fever vaccine-associated viscerotropic disease (YEL-AVD). Initial investigations focused on the possibility that the live vaccine virus had reverted to virulence but found no conclusive evidence this had occurred [6]. The 17D vaccine is genetically heterogeneous, but the consensus genetic sequences obtained from people with YEL-AVD have shown remarkable stability and concordance with reference vaccine strain sequences [1,6,7]. Cases of suspected YEL-AVD have been retrospectively discovered from as early as 1973 [8,9]. To date, the most plausible conclusions about YEL-AVD are that it has probably occurred rarely and without detection throughout the years of 17D vaccine use, and that it is most likely a consequence of injecting a live yellow fever vaccine into a person who, because of inherited or acquired susceptibility, fails to control the proliferation of the vaccine virus. YEL-AVD is relatively rare; the estimated frequency in the United States is 0.4 per 100,000 vaccine doses, and limited data suggest that it is has also been rare during vaccination campaigns in Africa [10,11]. However, during a recent vaccination campaign in Peru the incidence was 7.9 per 100,000 doses [7]. To put this in context with a severe adverse event from another commonly used live vaccine, the reported frequency of vaccineassociated paralytic poliomyelitis (VAPP) after first doses of live oral polio vaccination from 1990 to 1999 in the United States, including
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cases among contacts of vaccine recipients, was 0.11 per 100,000 doses [12]. Two other rare but severe adverse events after 17D vaccination are anaphylactic reactions and yellow-fever-vaccine-associated neurologic disease (YEL-AND). Anaphylaxis occurs at a frequency of about 1.8 per 100,000 doses and is thought to be mostly attributable to allergy to proteins from eggs or gelatin used in vaccine production [1,10,13]. YEL-AND can manifest as encephalitis, meningitis, neuropathy, Guillain-Barre syndrome, acute disseminated encephalomyelitis, or spinal myelitis. The case fatality rate of YEL-AND appears to be relatively low; of 28 cases in one review, 1 fatality was reported in a man with underlying human immunodeficiency virus infection [1]. Estimates of the frequency of YEL-AND have ranged from 0.4 to 9.9 per 100,000 doses depending on the study and case definition used [1,10,14]. Overall, the risk of any severe adverse event after yellow fever vaccination of travelers in the United States is about 4.7 per 100,000 but is higher among vaccine recipients 60 years of age or older (8.3 per 100,000 doses) [10]. In the face of a yellow fever outbreak this adverse event risk is very low, and most severe adverse events, apart from YEL-AVD, are not generally as threatening as yellow fever. Nevertheless, the risk of severe adverse events among older travelers is concerning when compared to the risk that a traveler to endemic areas in South America will acquire yellow fever (roughly estimated at 5 per 100,000 travelers for a 2 week trip) [1,15]. Two recent reports raise further concern about 17D vaccine safety. In January 2010, the Centers for Disease Control and Prevention (CDC) reported transmission of 17D virus through accidental transfusion of blood products from recently vaccinated donors [16]. This risk had been recognized on theoretical grounds but had not been previously demonstrated. In February 2010, the CDC published a report of encephalitis in an infant in Brazil who acquired yellow fever vaccine virus through breastfeeding [17]. The risk of 17D virus transmission through breastfeeding had also been recognized on theoretical grounds, but this is the first confirmation that such transmission can cause illness in an infant [17]. Although congenital infection with the 17D vaccine can apparently occur, thus far the vaccine has not been shown to adversely affect infants of mothers who were vaccinated during pregnancy [1,18]. The risks of nonintentional vaccine transmission are inherent to 17D because it is a live vaccine. Theoretically, the newly developed chimeric vaccines against Japanese encephalitis, dengue and West Nile virus disease that use a 17D virus strain as their backbone could carry similar risks of non-intentional transmission, although the level of viremia elicited by these vaccines appears to be comparatively low [19]. Because of a higher risk of YEL-AND in young infants (the estimated risk ranges from 0.5 to 4 per 1,000 vaccinations) [1], the 17D vaccine is contraindicated for infants less than 6 months of age, and is not generally recommended for infants less than 9 months of age, thus leaving an important age gap in protective utility of the vaccine [1,33]. In addition, the 17D vaccine is contraindicated for people who are immunocompromised. While the vaccine has been safely administered to people with asymptomatic HIV infection who have adequate CD4 counts, it is contraindicated for people with symptomatic HIV infection, representing a public health barrier to protection against yellow fever in endemic areas where HIV infection is prevalent. According to the Joint United Nations Programme on HIV/AIDS, in 2007, there were over 9 million people living with HIV infection in African countries considered by CDC to have endemic yellow fever (http://www.unaids.org/en/ KnowledgeCentre/HIVData/Epidemiology/latestEpiData.asp and http://wwwn.cdc.gov/travel/yellowBookCh4-YellowFever.aspx# 668). An inactivated yellow fever vaccine could circumvent many of the safety concerns regarding 17D vaccine. A safe and effective inactivated vaccine might be considered for use either as
an alternative to live attenuated vaccine, or as a priming vaccine, and could be targeted to persons who are at higher risk of adverse events from the live vaccine or offered more universally. In 1928, Hindle [20] described development of an inactivated vaccine made from liver and spleen taken from a monkey who had died of yellow fever. The infected tissue was macerated and treated with formaldehyde in one preparation and with phenol in another. Both preparations appeared to protect monkeys against yellow fever, but subsequent investigations of efficacy were inconclusive [1,20]. The techniques and immunologic knowledge for preparing these and other early inactivated vaccines were rudimentary, and these efforts soon yielded to the development of live attenuated vaccines [1]. The recent safety concerns regarding 17D have spurred renewed efforts to develop inactivated vaccines from attenuated vaccine strains with modern methods. In 2008, Gaspar et al. [21] described pressure inactivation of 17DD vaccine virus. The product caused no mortality in 20 mice following intracerebral inoculation compared to 100% mortality among 20 mice inoculated with live 17DD vaccine virus, suggesting that the inactivated preparation did not contain residual live virus. The inactivated vaccine elicited lower levels of neutralizing antibody than the live virus vaccine but did protect mice from intracerebral challenge with live 17DD virus. In 2010, Monath et al. [22] described development of an inactivated whole virion vaccine using 17D virus that was inactivated with beta-propiolactone and adsorbed to aluminum hydroxide. Loss of infectivity was demonstrated by plaque assay. Inoculated rats developed inflammation at injection sites, lymph nodes and the spleen, but had no serious toxicity that would impede plans to test the vaccine in humans. All the rats developed neutralizing antibodies. The inactivated vaccine was also immunogenic in mice and hamsters. The hamsters developed neutralizing antibody titers similar to or higher than titers after live 17D vaccination and were protected against challenge with wild-type yellow fever virus. One dose of the vaccine elicited high neutralizing antibody titers at day 21 after inoculation in two of three monkeys, and two doses elicited high levels of antibody at day 21 in three other monkeys. Neutralizing antibody persisted at day 42 in all monkeys. A trial of the vaccine in humans is under way [22]. To borrow a phrase from John Irving’s novel The Cider House Rules, would an inactive yellow fever vaccine “be of use”? An inactivated vaccine would be appealing for vaccination of travelers, particularly those over 60 years of age, since their exposure to yellow fever is generally transient, and their risk of severe adverse events after vaccination for some itineraries can approximate their risk of acquiring yellow fever. But would an inactivated vaccine be of any global public health use? The pros and cons of inactivated vaccine compared to live vaccine have been extensively debated in the context of global efforts to control polio [23,24]. The estimated risk of VAPP that provoked cessation of live polio vaccine use in the United States was lower than the current estimated rate of YEL-AVD [10,25]. While VAPP can cause severe disability, the case-fatality rate of YEL-AVD is notably higher [1,26]. However, the policies in favor of use of inactivated polio vaccine are also influenced by the risk of person-to-person transmission of vaccine-derived polioviruses [24,25]. Apart from the rare instances of non-intentional transmission mentioned above, live yellow fever vaccination does not raise this concern. An inactivated yellow fever vaccine would most likely be injectable so there would be little difference between an inactivated vaccine and the 17D vaccine regarding ease of inoculation. Thus, the principle determinants of the relative usefulness of a new inactivated yellow fever vaccine are reduced to three factors that must be compared against the current 17D vaccine: effectiveness, safety, and cost.
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The initial studies in animals described above suggest that an inactivated vaccine could be effectively immunogenetic, but data in humans are needed to confirm this [22]. The effectiveness of the live 17D vaccine in preventing yellow fever has never been assessed through a controlled trial. Nevertheless, it is unlikely that an inactivated vaccine could fully match the long-term protection provided by a single dose of live 17D. The actual duration of immunity following live 17D vaccination remains unclear, but limited evidence suggests that vaccine-elicited neutralizing antibody is detectable for at least 30 years, and experts have postulated that immunity might be lifelong [1,27]. Multiple doses of inactivated vaccine would probably be required to achieve and maintain similar long-lasting immunity. The live 17D vaccine is well suited to provide high population coverage of lasting protective immunity against yellow fever in endemic areas. Providing similar coverage through multiple doses of an inactivated vaccine would require additional effort and expense. Mathematical models might help predict the short and long-term effects of varying coverage and numbers of doses of inactivated vaccine compared with a single dose of live vaccine on the incidence of yellow fever [28–30]. On theoretical grounds, it is likely that an inactivated vaccine would be safer than the live 17D vaccine. In addition to reducing risk of YEL-AVD and YEL-AND, the risk of anaphylaxis might be lowered using Vero cells instead of eggs and gelatin in vaccine manufacture. A safe inactivated vaccine could provide protection against yellow fever for people who might fall in a “protection gap”: young infants and immunocompromised people, for whom the live 17D vaccine is contraindicated; as well as pregnant and breastfeeding women; and people over 60 years of age, for whom risks of vaccination outweigh benefits when the risk of yellow fever is low. It would seem reasonable to incorporate inactivated vaccine into mass preventive and emergency response vaccination campaigns in order to safely cover these population sub-groups. In such a scenario, the majority of the population could be vaccinated with the live 17D vaccine but the subgroups at higher risk of adverse events could receive inactivated vaccine. Alternatively, an inactivated vaccine might be used for primary vaccination in hopes of reducing the risk of YEL-AVD following subsequent live 17D vaccination, but the safety of this strategy would need to be assessed. The appeal of a safer inactivated vaccine has global health implications. Determining the need for mass vaccination of populations living near yellow-fever-endemic areas is currently controversial, requiring that public-health officials balance the risk of yellow fever spread against the risk of severe adverse events following mass vaccination [7,31]. A safer inactivated vaccine could tip the balance towards encouraging mass immunization of populations with potential but not immediate risk of yellow fever, thus improving global protection against the spread of yellow fever. In addition, some country-entry requirements for yellow fever vaccination, intended to limit spread of yellow fever , are being legitimately questioned because they can place travelers at risk of adverse events from vaccination in exchange for virtually no personal protective value (as when traveling to an area that is infested with vector mosquitoes but not endemic for yellow fever) [32]. A safer inactivated vaccine would lower the risk of adverse events for individual travelers and thus strengthen the rationale for maintaining country-entry vaccine requirements designed to protect resident populations against the introduction of yellow fever virus. The arguments in favor of development of inactivated vaccine will have to be weighed against the cost of the vaccine. Given the current high costs of vaccine development, can an inactivated vaccine be sold at a price accessible to public-health efforts, such as mass preventive vaccination or epidemic response? It is time for a new yellow fever vaccine, at least for the “traveler’s market”, but
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whether or not a new vaccine is of use to global health will be highly dependent on its cost. Acknowledgment The author thanks Dr. Erin Staples for helpful comments on the manuscript. References [1] Monath T, Cetron M, Teuwen D. Yellow fever vaccine. In: Plotkin S, Orenstein W, Offit P, editors. Vaccines. 5th ed. Saunders Elsevier; 2008. p. 959–1055. [2] Barrett ADT, Teuwen DE. Yellow fever vaccine—how does it work and why do rare cases of serious adverse events take place? Curr Opin Immunol 2009;21(3):308–13. [3] Vasconcelos PF, Luna EJ, Galler R, Silva LJ, Coimbra TL, Barros VL, et al. Serious adverse events associated with yellow fever 17DD vaccine in Brazil: a report of two cases. Lancet 2001;358(9276):91–7. [4] Martin M, Tsai TF, Cropp B, Chang GJ, Holmes DA, Tseng J, et al. Fever and multisystem organ failure associated with 17D-204 yellow fever vaccination: a report of four cases. Lancet 2001;358(9276):98–104. [5] Chan RC, Penney DJ, Little D, Carter IW, Roberts JA, Rawlinson WD. Hepatitis and death following vaccination with 17D-204 yellow fever vaccine. Lancet 2001;358(9276):121–2. [6] Hayes EB. Acute viscerotropic disease following vaccination against yellow fever. Trans R Soc Trop Med Hyg 2007;101(10):967–71. [7] Whittembury A, Ramirez G, Hernández H, Ropero AM, Waterman S, Ticona M, et al. Viscerotropic disease following yellow fever vaccination in Peru. Vaccine 2009;27(43):5974–81. [8] Monath TP. Suspected yellow fever vaccine-associated viscerotropic adverse events (1973 and 1978) United States. Am J Trop Med Hyg 2010;82(5):919–21. [9] Engel AR, Vasconcelos PFC, McArthur MA, Barrett ADT. Characterization of a viscerotropic yellow fever vaccine variant from a patient in Brazil. Vaccine 2006;24(15):2803–9. [10] Lindsey NP, Schroeder BA, Miller ER, Braun MM, Hinckley AF, Marano N, et al. Adverse event reports following yellow fever vaccination. Vaccine 2008;26(48):6077–82. [11] Fitzner J, Coulibaly D, Kouadio DE, Yavo JC, Loukou YG, Koudou PO, et al. Safety of the yellow fever vaccine during the September 2001 mass vaccination campaign in Abidjan Ivory Coast. Vaccine 2004;23(2):156–62. [12] Alexander LN, Seward JF, Santibanez TA, Pallansch MA, Kew OM, Prevots DR, et al. Vaccine policy changes and epidemiology of poliomyelitis in the United States. JAMA 2004;292(14):1696–701. [13] Kelso JM, Mootrey GT, Tsai TF. Anaphylaxis from yellow fever vaccine. J Allergy Clin Immunol 1999;103(4):698–701. [14] Guimard T, Minjolle S, Polard E, Fily F, Zeller H, Michelet C, et al. Short report: incidence of yellow fever vaccine-associated neurotropic disease. Am J Trop Med Hyg 2009;81(6):1141–3. [15] Monath TP, Cetron MS. Prevention of yellow fever in persons traveling to the tropics. Clin Infect Dis 2002;34(10):1369–78. [16] Transfusion-related transmission of yellow fever vaccine virus—California, 2009. Morb Mortal Wkly Rep 2010;59(2):34–7. [17] Transmission of yellow fever vaccine virus through breast-feeding—Brazil, 2009. Morb Mortal Wkly Rep 2010;59(5):130–2. [18] Tsai TF, Paul R, Lynberg MC, Letson GW. Congenital yellow fever virus infection after immunization in pregnancy. J Infect Dis 1993;168(6):1520–3. [19] Guy B, Guirakhoo F, Barban V, Higgs S, Monath TP, Lang J. Preclinical and clinical development of YFV 17D-based chimeric vaccines against dengue West Nile and Japanese encephalitis viruses. Vaccine 2010;28(3):632–49. [20] Hindle E. A yellow fever vaccine. Br Med J 1928;1(3518):976–7. [21] Gaspar LP, Mendes YS, Yamamura AMY, Almeida LFC, Caride E, Gonc¸alves RB, et al. Pressure-inactivated yellow fever 17DD virus: implications for vaccine development. J Virol Methods 2008;150(1–2):57–62. [22] Monath TP, Lee CK, Julander JG, Brown A, Beasley DW, Watts DM, et al. Inactivated yellow fever 17D vaccine: development and nonclinical safety, immunogenicity and protective activity. Vaccine 2010;28(22):3827–40. [23] Minor P. Vaccine-derived poliovirus (VDPV): impact on poliomyelitis eradication. Vaccine 2009;27(20):2649–52. [24] John J. Role of injectable and oral polio vaccines in polio eradication. Expert Rev Vaccines 2009;8(1):5–8. [25] Poliomyelitis prevention in the United States: introduction of a sequential vaccination schedule of inactivated poliovirus vaccine followed by oral poliovirus vaccine. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 1997;46(RR-3):1–25. [26] Update: outbreak of poliomyelitis—Dominican Republic and Haiti, 2000–2001. MMWR Morb Mortal Wkly Rep 2001;50(39):855–6. [27] Poland JD, Calisher CH, Monath TP, Downs WG, Murphy K. Persistence of neutralizing antibody 30–35 years after immunization with 17D yellow fever vaccine. Bull World Health Organ 1981;59(6):895–900. [28] Chaib E, de Oliveira MCF, Galvão FHF, Silva FD, D’Albuquerque LAC, Massad E. Theoretical impact of an anti-HCV vaccine on the annual number of liver transplantation. Med Hypotheses 2010;75(3):324–7.
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[29] Bauch CT, Li M, Chapman G, Galvani AP. Adherence to cervical screening in the era of human papillomavirus vaccination: how low is too low? Lancet Infect Dis 2010;10(2):133–7. [30] Ziv E, Daley CL, Blower S. Potential public health impact of new tuberculosis vaccines. Emerging Infect Dis 2004;10(9):1529–35. [31] Massad E, Coutinho FAB, Burattini MN, Lopez LF, Struchiner CJ. Yellow fever vaccination: how much is enough? Vaccine 2005;23(30):3908–14.
[32] Douce RW, Freire D, Tello B, Vásquez GA. A case of yellow fever vaccine-associated viscerotropic disease in Ecuador. Am J Trop Med Hyg 2010;82(4):740–2. [33] Staples JE, Gershman M, Fischer M. Yellow fever vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2010;59(RR-7):1–27.
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Review
Is it time for a new yellow fever vaccine? Edward B. Hayes ∗ Barcelona Centre for International Health Research, Rosselo 132, 08036 Barcelona, Spain
a r t i c l e
i n f o
Article history: Received 17 June 2010 Received in revised form 7 September 2010 Accepted 7 October 2010 Available online 3 November 2010 Keywords: Yellow fever Yellow fever vaccine Global health Traveler’s health Flavivirus vaccine
a b s t r a c t An inexpensive live attenuated vaccine (the 17D vaccine) against yellow fever has been effectively used to prevent yellow fever for more than 70 years. Interest in developing new inactivated vaccines has been spurred by recognition of rare but serious, sometimes fatal adverse events following live virus vaccination. A safer inactivated yellow fever vaccine could be useful for vaccinating people at higher risk of adverse events from the live vaccine, but could also have broader global health utility by lowering the riskbenefit threshold for assuring high levels of yellow fever vaccine coverage. If ongoing trials demonstrate favorable immunogenicity and safety compared to the current vaccine, the practical global health utility of an inactivated vaccine is likely to be determined mostly by cost. © 2010 Elsevier Ltd. All rights reserved.
Contents Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8075 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8075
Yellow fever is one of the great infectious scourges of humankind, ranking in historical impact with plague and smallpox. It is a fearsome disease and, unlike smallpox, has never been fully controlled. Yellow fever virus is endemically transmitted in forests and savannas of South America and Africa, periodically emerging from enzootic cycles to cause epidemics of hemorrhagic fever with case fatality rates ranging from 20% to 50% [1]. Thousands of cases of yellow fever are reported to WHO each year from tropical areas of Africa and South America, and rare sporadic cases occur among travelers to endemic areas. The 17D live attenuated yellow fever virus vaccine was developed in the 1930s through work that was recognized with a Nobel Prize awarded to Max Theiler in 1951. The vaccine was used in field trials in 1937, and over the intervening 73 years has been given to more than 500 million people and considered one of the most effective and safe vaccines ever developed [2]. A single dose of 17D yellow fever vaccine confers long-term immunity, and costs less than one U.S. dollar for use in endemic countries [1]. All that seems hard to beat, so do we need another yellow fever vaccine? In 2001 three articles first described a new type of serious adverse event after yellow fever vaccination [3–5]. The vaccine
∗ Tel.: +34 93 227 1852. E-mail address: [email protected] 0264-410X/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2010.10.015
recipients developed an illness that closely resembled wild type yellow fever and had a similarly high fatality rate. This multiorgan system failure after vaccination was later named yellow fever vaccine-associated viscerotropic disease (YEL-AVD). Initial investigations focused on the possibility that the live vaccine virus had reverted to virulence but found no conclusive evidence this had occurred [6]. The 17D vaccine is genetically heterogeneous, but the consensus genetic sequences obtained from people with YEL-AVD have shown remarkable stability and concordance with reference vaccine strain sequences [1,6,7]. Cases of suspected YEL-AVD have been retrospectively discovered from as early as 1973 [8,9]. To date, the most plausible conclusions about YEL-AVD are that it has probably occurred rarely and without detection throughout the years of 17D vaccine use, and that it is most likely a consequence of injecting a live yellow fever vaccine into a person who, because of inherited or acquired susceptibility, fails to control the proliferation of the vaccine virus. YEL-AVD is relatively rare; the estimated frequency in the United States is 0.4 per 100,000 vaccine doses, and limited data suggest that it is has also been rare during vaccination campaigns in Africa [10,11]. However, during a recent vaccination campaign in Peru the incidence was 7.9 per 100,000 doses [7]. To put this in context with a severe adverse event from another commonly used live vaccine, the reported frequency of vaccineassociated paralytic poliomyelitis (VAPP) after first doses of live oral polio vaccination from 1990 to 1999 in the United States, including
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cases among contacts of vaccine recipients, was 0.11 per 100,000 doses [12]. Two other rare but severe adverse events after 17D vaccination are anaphylactic reactions and yellow-fever-vaccine-associated neurologic disease (YEL-AND). Anaphylaxis occurs at a frequency of about 1.8 per 100,000 doses and is thought to be mostly attributable to allergy to proteins from eggs or gelatin used in vaccine production [1,10,13]. YEL-AND can manifest as encephalitis, meningitis, neuropathy, Guillain-Barre syndrome, acute disseminated encephalomyelitis, or spinal myelitis. The case fatality rate of YEL-AND appears to be relatively low; of 28 cases in one review, 1 fatality was reported in a man with underlying human immunodeficiency virus infection [1]. Estimates of the frequency of YEL-AND have ranged from 0.4 to 9.9 per 100,000 doses depending on the study and case definition used [1,10,14]. Overall, the risk of any severe adverse event after yellow fever vaccination of travelers in the United States is about 4.7 per 100,000 but is higher among vaccine recipients 60 years of age or older (8.3 per 100,000 doses) [10]. In the face of a yellow fever outbreak this adverse event risk is very low, and most severe adverse events, apart from YEL-AVD, are not generally as threatening as yellow fever. Nevertheless, the risk of severe adverse events among older travelers is concerning when compared to the risk that a traveler to endemic areas in South America will acquire yellow fever (roughly estimated at 5 per 100,000 travelers for a 2 week trip) [1,15]. Two recent reports raise further concern about 17D vaccine safety. In January 2010, the Centers for Disease Control and Prevention (CDC) reported transmission of 17D virus through accidental transfusion of blood products from recently vaccinated donors [16]. This risk had been recognized on theoretical grounds but had not been previously demonstrated. In February 2010, the CDC published a report of encephalitis in an infant in Brazil who acquired yellow fever vaccine virus through breastfeeding [17]. The risk of 17D virus transmission through breastfeeding had also been recognized on theoretical grounds, but this is the first confirmation that such transmission can cause illness in an infant [17]. Although congenital infection with the 17D vaccine can apparently occur, thus far the vaccine has not been shown to adversely affect infants of mothers who were vaccinated during pregnancy [1,18]. The risks of nonintentional vaccine transmission are inherent to 17D because it is a live vaccine. Theoretically, the newly developed chimeric vaccines against Japanese encephalitis, dengue and West Nile virus disease that use a 17D virus strain as their backbone could carry similar risks of non-intentional transmission, although the level of viremia elicited by these vaccines appears to be comparatively low [19]. Because of a higher risk of YEL-AND in young infants (the estimated risk ranges from 0.5 to 4 per 1,000 vaccinations) [1], the 17D vaccine is contraindicated for infants less than 6 months of age, and is not generally recommended for infants less than 9 months of age, thus leaving an important age gap in protective utility of the vaccine [1,33]. In addition, the 17D vaccine is contraindicated for people who are immunocompromised. While the vaccine has been safely administered to people with asymptomatic HIV infection who have adequate CD4 counts, it is contraindicated for people with symptomatic HIV infection, representing a public health barrier to protection against yellow fever in endemic areas where HIV infection is prevalent. According to the Joint United Nations Programme on HIV/AIDS, in 2007, there were over 9 million people living with HIV infection in African countries considered by CDC to have endemic yellow fever (http://www.unaids.org/en/ KnowledgeCentre/HIVData/Epidemiology/latestEpiData.asp and http://wwwn.cdc.gov/travel/yellowBookCh4-YellowFever.aspx# 668). An inactivated yellow fever vaccine could circumvent many of the safety concerns regarding 17D vaccine. A safe and effective inactivated vaccine might be considered for use either as
an alternative to live attenuated vaccine, or as a priming vaccine, and could be targeted to persons who are at higher risk of adverse events from the live vaccine or offered more universally. In 1928, Hindle [20] described development of an inactivated vaccine made from liver and spleen taken from a monkey who had died of yellow fever. The infected tissue was macerated and treated with formaldehyde in one preparation and with phenol in another. Both preparations appeared to protect monkeys against yellow fever, but subsequent investigations of efficacy were inconclusive [1,20]. The techniques and immunologic knowledge for preparing these and other early inactivated vaccines were rudimentary, and these efforts soon yielded to the development of live attenuated vaccines [1]. The recent safety concerns regarding 17D have spurred renewed efforts to develop inactivated vaccines from attenuated vaccine strains with modern methods. In 2008, Gaspar et al. [21] described pressure inactivation of 17DD vaccine virus. The product caused no mortality in 20 mice following intracerebral inoculation compared to 100% mortality among 20 mice inoculated with live 17DD vaccine virus, suggesting that the inactivated preparation did not contain residual live virus. The inactivated vaccine elicited lower levels of neutralizing antibody than the live virus vaccine but did protect mice from intracerebral challenge with live 17DD virus. In 2010, Monath et al. [22] described development of an inactivated whole virion vaccine using 17D virus that was inactivated with beta-propiolactone and adsorbed to aluminum hydroxide. Loss of infectivity was demonstrated by plaque assay. Inoculated rats developed inflammation at injection sites, lymph nodes and the spleen, but had no serious toxicity that would impede plans to test the vaccine in humans. All the rats developed neutralizing antibodies. The inactivated vaccine was also immunogenic in mice and hamsters. The hamsters developed neutralizing antibody titers similar to or higher than titers after live 17D vaccination and were protected against challenge with wild-type yellow fever virus. One dose of the vaccine elicited high neutralizing antibody titers at day 21 after inoculation in two of three monkeys, and two doses elicited high levels of antibody at day 21 in three other monkeys. Neutralizing antibody persisted at day 42 in all monkeys. A trial of the vaccine in humans is under way [22]. To borrow a phrase from John Irving’s novel The Cider House Rules, would an inactive yellow fever vaccine “be of use”? An inactivated vaccine would be appealing for vaccination of travelers, particularly those over 60 years of age, since their exposure to yellow fever is generally transient, and their risk of severe adverse events after vaccination for some itineraries can approximate their risk of acquiring yellow fever. But would an inactivated vaccine be of any global public health use? The pros and cons of inactivated vaccine compared to live vaccine have been extensively debated in the context of global efforts to control polio [23,24]. The estimated risk of VAPP that provoked cessation of live polio vaccine use in the United States was lower than the current estimated rate of YEL-AVD [10,25]. While VAPP can cause severe disability, the case-fatality rate of YEL-AVD is notably higher [1,26]. However, the policies in favor of use of inactivated polio vaccine are also influenced by the risk of person-to-person transmission of vaccine-derived polioviruses [24,25]. Apart from the rare instances of non-intentional transmission mentioned above, live yellow fever vaccination does not raise this concern. An inactivated yellow fever vaccine would most likely be injectable so there would be little difference between an inactivated vaccine and the 17D vaccine regarding ease of inoculation. Thus, the principle determinants of the relative usefulness of a new inactivated yellow fever vaccine are reduced to three factors that must be compared against the current 17D vaccine: effectiveness, safety, and cost.
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The initial studies in animals described above suggest that an inactivated vaccine could be effectively immunogenetic, but data in humans are needed to confirm this [22]. The effectiveness of the live 17D vaccine in preventing yellow fever has never been assessed through a controlled trial. Nevertheless, it is unlikely that an inactivated vaccine could fully match the long-term protection provided by a single dose of live 17D. The actual duration of immunity following live 17D vaccination remains unclear, but limited evidence suggests that vaccine-elicited neutralizing antibody is detectable for at least 30 years, and experts have postulated that immunity might be lifelong [1,27]. Multiple doses of inactivated vaccine would probably be required to achieve and maintain similar long-lasting immunity. The live 17D vaccine is well suited to provide high population coverage of lasting protective immunity against yellow fever in endemic areas. Providing similar coverage through multiple doses of an inactivated vaccine would require additional effort and expense. Mathematical models might help predict the short and long-term effects of varying coverage and numbers of doses of inactivated vaccine compared with a single dose of live vaccine on the incidence of yellow fever [28–30]. On theoretical grounds, it is likely that an inactivated vaccine would be safer than the live 17D vaccine. In addition to reducing risk of YEL-AVD and YEL-AND, the risk of anaphylaxis might be lowered using Vero cells instead of eggs and gelatin in vaccine manufacture. A safe inactivated vaccine could provide protection against yellow fever for people who might fall in a “protection gap”: young infants and immunocompromised people, for whom the live 17D vaccine is contraindicated; as well as pregnant and breastfeeding women; and people over 60 years of age, for whom risks of vaccination outweigh benefits when the risk of yellow fever is low. It would seem reasonable to incorporate inactivated vaccine into mass preventive and emergency response vaccination campaigns in order to safely cover these population sub-groups. In such a scenario, the majority of the population could be vaccinated with the live 17D vaccine but the subgroups at higher risk of adverse events could receive inactivated vaccine. Alternatively, an inactivated vaccine might be used for primary vaccination in hopes of reducing the risk of YEL-AVD following subsequent live 17D vaccination, but the safety of this strategy would need to be assessed. The appeal of a safer inactivated vaccine has global health implications. Determining the need for mass vaccination of populations living near yellow-fever-endemic areas is currently controversial, requiring that public-health officials balance the risk of yellow fever spread against the risk of severe adverse events following mass vaccination [7,31]. A safer inactivated vaccine could tip the balance towards encouraging mass immunization of populations with potential but not immediate risk of yellow fever, thus improving global protection against the spread of yellow fever. In addition, some country-entry requirements for yellow fever vaccination, intended to limit spread of yellow fever , are being legitimately questioned because they can place travelers at risk of adverse events from vaccination in exchange for virtually no personal protective value (as when traveling to an area that is infested with vector mosquitoes but not endemic for yellow fever) [32]. A safer inactivated vaccine would lower the risk of adverse events for individual travelers and thus strengthen the rationale for maintaining country-entry vaccine requirements designed to protect resident populations against the introduction of yellow fever virus. The arguments in favor of development of inactivated vaccine will have to be weighed against the cost of the vaccine. Given the current high costs of vaccine development, can an inactivated vaccine be sold at a price accessible to public-health efforts, such as mass preventive vaccination or epidemic response? It is time for a new yellow fever vaccine, at least for the “traveler’s market”, but
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whether or not a new vaccine is of use to global health will be highly dependent on its cost. Acknowledgment The author thanks Dr. Erin Staples for helpful comments on the manuscript. References [1] Monath T, Cetron M, Teuwen D. Yellow fever vaccine. In: Plotkin S, Orenstein W, Offit P, editors. Vaccines. 5th ed. Saunders Elsevier; 2008. p. 959–1055. [2] Barrett ADT, Teuwen DE. Yellow fever vaccine—how does it work and why do rare cases of serious adverse events take place? Curr Opin Immunol 2009;21(3):308–13. [3] Vasconcelos PF, Luna EJ, Galler R, Silva LJ, Coimbra TL, Barros VL, et al. Serious adverse events associated with yellow fever 17DD vaccine in Brazil: a report of two cases. Lancet 2001;358(9276):91–7. [4] Martin M, Tsai TF, Cropp B, Chang GJ, Holmes DA, Tseng J, et al. Fever and multisystem organ failure associated with 17D-204 yellow fever vaccination: a report of four cases. Lancet 2001;358(9276):98–104. [5] Chan RC, Penney DJ, Little D, Carter IW, Roberts JA, Rawlinson WD. Hepatitis and death following vaccination with 17D-204 yellow fever vaccine. Lancet 2001;358(9276):121–2. [6] Hayes EB. Acute viscerotropic disease following vaccination against yellow fever. Trans R Soc Trop Med Hyg 2007;101(10):967–71. [7] Whittembury A, Ramirez G, Hernández H, Ropero AM, Waterman S, Ticona M, et al. Viscerotropic disease following yellow fever vaccination in Peru. Vaccine 2009;27(43):5974–81. [8] Monath TP. Suspected yellow fever vaccine-associated viscerotropic adverse events (1973 and 1978) United States. Am J Trop Med Hyg 2010;82(5):919–21. [9] Engel AR, Vasconcelos PFC, McArthur MA, Barrett ADT. Characterization of a viscerotropic yellow fever vaccine variant from a patient in Brazil. Vaccine 2006;24(15):2803–9. [10] Lindsey NP, Schroeder BA, Miller ER, Braun MM, Hinckley AF, Marano N, et al. Adverse event reports following yellow fever vaccination. Vaccine 2008;26(48):6077–82. [11] Fitzner J, Coulibaly D, Kouadio DE, Yavo JC, Loukou YG, Koudou PO, et al. Safety of the yellow fever vaccine during the September 2001 mass vaccination campaign in Abidjan Ivory Coast. Vaccine 2004;23(2):156–62. [12] Alexander LN, Seward JF, Santibanez TA, Pallansch MA, Kew OM, Prevots DR, et al. Vaccine policy changes and epidemiology of poliomyelitis in the United States. JAMA 2004;292(14):1696–701. [13] Kelso JM, Mootrey GT, Tsai TF. Anaphylaxis from yellow fever vaccine. J Allergy Clin Immunol 1999;103(4):698–701. [14] Guimard T, Minjolle S, Polard E, Fily F, Zeller H, Michelet C, et al. Short report: incidence of yellow fever vaccine-associated neurotropic disease. Am J Trop Med Hyg 2009;81(6):1141–3. [15] Monath TP, Cetron MS. Prevention of yellow fever in persons traveling to the tropics. Clin Infect Dis 2002;34(10):1369–78. [16] Transfusion-related transmission of yellow fever vaccine virus—California, 2009. Morb Mortal Wkly Rep 2010;59(2):34–7. [17] Transmission of yellow fever vaccine virus through breast-feeding—Brazil, 2009. Morb Mortal Wkly Rep 2010;59(5):130–2. [18] Tsai TF, Paul R, Lynberg MC, Letson GW. Congenital yellow fever virus infection after immunization in pregnancy. J Infect Dis 1993;168(6):1520–3. [19] Guy B, Guirakhoo F, Barban V, Higgs S, Monath TP, Lang J. Preclinical and clinical development of YFV 17D-based chimeric vaccines against dengue West Nile and Japanese encephalitis viruses. Vaccine 2010;28(3):632–49. [20] Hindle E. A yellow fever vaccine. Br Med J 1928;1(3518):976–7. [21] Gaspar LP, Mendes YS, Yamamura AMY, Almeida LFC, Caride E, Gonc¸alves RB, et al. Pressure-inactivated yellow fever 17DD virus: implications for vaccine development. J Virol Methods 2008;150(1–2):57–62. [22] Monath TP, Lee CK, Julander JG, Brown A, Beasley DW, Watts DM, et al. Inactivated yellow fever 17D vaccine: development and nonclinical safety, immunogenicity and protective activity. Vaccine 2010;28(22):3827–40. [23] Minor P. Vaccine-derived poliovirus (VDPV): impact on poliomyelitis eradication. Vaccine 2009;27(20):2649–52. [24] John J. Role of injectable and oral polio vaccines in polio eradication. Expert Rev Vaccines 2009;8(1):5–8. [25] Poliomyelitis prevention in the United States: introduction of a sequential vaccination schedule of inactivated poliovirus vaccine followed by oral poliovirus vaccine. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 1997;46(RR-3):1–25. [26] Update: outbreak of poliomyelitis—Dominican Republic and Haiti, 2000–2001. MMWR Morb Mortal Wkly Rep 2001;50(39):855–6. [27] Poland JD, Calisher CH, Monath TP, Downs WG, Murphy K. Persistence of neutralizing antibody 30–35 years after immunization with 17D yellow fever vaccine. Bull World Health Organ 1981;59(6):895–900. [28] Chaib E, de Oliveira MCF, Galvão FHF, Silva FD, D’Albuquerque LAC, Massad E. Theoretical impact of an anti-HCV vaccine on the annual number of liver transplantation. Med Hypotheses 2010;75(3):324–7.
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