Rabies vaccinations save lives but where are the vaccines? Global vaccine inequity and escalating rabies-related mortality in low- and middle-income countries

Abstract

Human rabies (Sanskrit "rabhas", to do violence; Latin "rabere", to rage) is an ancient scourge which claims the lives of tens of thousands of people per year worldwide. Numbers of clinical cases and deaths are grossly under-reported due to diagnostic limitations in low-and middle-income countries (LMICs) which are endemic for rabies [[1]Henry R. Etymologia: Rabies.Emerg Infect Dis. 2012; 18: 1169https://doi.org/10.3201/eid1807.ET1807Crossref Google Scholar,[2]Pantha S Subedi D Poudel U Subedi S Kaphle K Dhakal S. Review of rabies in Nepal.One Health. 2020; 10: 1-8https://doi.org/10.1016/j.onehlt.2020.100155Crossref Scopus (28) Google Scholar]. Rabies remains a significant yet neglected public health problem, particularly in LMICs with children under 15 years of age representing 40% of annual fatalities [[3]Amoako YA El-Duah P Sylverken AA Owusu M Yeboah R Gorman R et al.Rabies is still a fatal but neglected disease: a case report.J Med Case Rep. 2021; 15 (575): 1-6https://doi.org/10.1186/s13256-021-03164-yCrossref Scopus (6) Google Scholar]. While bites and scratches by infected dogs are the major cause of human rabies, hematophagous bats are emerging as important vectors for transmission of rabies virus (RABV) in the Americas as well as other Chiroptera and lyssavirus species in Africa, Eurasia and Australia [[4]Escobar LE Peterson AT Favi M Yung V Medina-Vogel G. Bat-borne rabies in Latin America.Rev Inst Med Trop Sao Paulo. 2015; 57: 63-72https://doi.org/10.1590/S0036-46652015000100009Crossref PubMed Scopus (45) Google Scholar]. The World Health Organization (WHO) has included rabies in its list of neglected tropical diseases targeted for elimination through its 2021 – 2030 roadmap, with the aim of zero human deaths due to dog-mediated rabies by 2030 [[5]WHO Rabies Modelling ConsortiumZero human deaths from dog-mediated rabies by 2030: perspectives from quantitative and mathematical modelling.Gates Open Res. 2020; 3: 1564https://doi.org/10.12688/gatesopenres.13074.2Crossref Scopus (9) Google Scholar]. Though a global decline in human rabies cases was noted in the three decades between 1990 – 2019 [[2]Pantha S Subedi D Poudel U Subedi S Kaphle K Dhakal S. Review of rabies in Nepal.One Health. 2020; 10: 1-8https://doi.org/10.1016/j.onehlt.2020.100155Crossref Scopus (28) Google Scholar], an alarming rise in diagnoses has been seen in the post-COVID-19 era in high-burden countries like India, where numbers of infected dogs, and unvaccinated and vaccinated humans have spiked significantly [[6]Goel K Sen A Satapathy P Kumar P Aggarwal AK Sah R et al.Emergence of rabies among vaccinated humans in India: a public health concern.Lancet Reg Health Southeast Asia. 2023; 100109https://doi.org/10.1016/j.lansea.2022.100109Abstract Full Text Full Text PDF Scopus (4) Google Scholar]. Large outbreaks have also been reported in other parts of the world since the COVID pandemic occurred. The eastern provinces of South Africa witnessed 430 cases of dog rabies and 17 confirmed human infections in the period between July 2021 – February 2022 while human rabies diagnoses have been made after a long hiatus in Brazil, Bhutan and Lebanon. Despite significant progress in the Americas as a whole, similar setbacks were also recognized in countries like Bolivia, Haiti and Peru [[6]Goel K Sen A Satapathy P Kumar P Aggarwal AK Sah R et al.Emergence of rabies among vaccinated humans in India: a public health concern.Lancet Reg Health Southeast Asia. 2023; 100109https://doi.org/10.1016/j.lansea.2022.100109Abstract Full Text Full Text PDF Scopus (4) Google Scholar,[7]Ravensberg MF Fanoy EB Whelan J Embregts CW GeurtsvanKessel CH Strydom JB. Ongoing rabies outbreak in dogs of unprecedented scale and human cases in Nelson Mandela Bay Municipality, South Africa, up to 13 February 2022.Euro Surveill. 2022; 272200252https://doi.org/10.2807/1560-7917.ES.2022.27.16.2200252Crossref Scopus (1) Google Scholar]. While rabies is vaccine-preventable, access to vaccines has challenged the implementation of pre- (PrEP) and post-exposure prophylaxis (PEP) programs in endemic countries. The cost of a complete PEP vaccine and immune globulin series exceeds USD65 – 108 per exposure, skewing the global supply towards countries which can afford it and away from African and Asian countries that are most vulnerable and for whom the life-saving vaccines are unaffordable [[4]Escobar LE Peterson AT Favi M Yung V Medina-Vogel G. Bat-borne rabies in Latin America.Rev Inst Med Trop Sao Paulo. 2015; 57: 63-72https://doi.org/10.1590/S0036-46652015000100009Crossref PubMed Scopus (45) Google Scholar,[8]Aklilu M Tadele W Alemu A Abdela S Getahun G Hailemariam A et al.Situation of Rabies in Ethiopia: A Five-Year Retrospective Study of Human Rabies in Addis Ababa and the Surrounding Regions.J Trop Med. 2021; 6662073https://doi.org/10.1155/2021/6662073Crossref Scopus (3) Google Scholar]. Moreover, while many nations have made a complete switch to the safer (less neuroparalytic adverse events), more immunogenic yet more expensive inactivated vaccines, some LMICs continue to give the outdated nerve-tissue derived vaccines [[9]WHO Rabies Modelling ConsortiumThe potential effect of improved provision of rabies post-exposure prophylaxis in Gavi-eligible countries: a modelling study.Lancet Infect Dis. 2019; 19: 102-111https://doi.org/10.1016/s1473-3099(18)30512-7Abstract Full Text Full Text PDF Google Scholar]. Without better access to modern and less expensive vaccines with dose-saving schedules, more than 1 million people are estimated to die from rabies in endemic countries from 2020 to 2035 [[8]Aklilu M Tadele W Alemu A Abdela S Getahun G Hailemariam A et al.Situation of Rabies in Ethiopia: A Five-Year Retrospective Study of Human Rabies in Addis Ababa and the Surrounding Regions.J Trop Med. 2021; 6662073https://doi.org/10.1155/2021/6662073Crossref Scopus (3) Google Scholar,[10]Natesan K Isloor S Vinayagamurthy B Ramakrishnaiah S Doddamane R Fooks AR. Developments in Rabies Vaccines: The Path Traversed from Pasteur to the Modern Era of Immunization.Vaccines. 2023; 11: 756https://doi.org/10.3390/vaccines11040756Crossref Scopus (3) Google Scholar]. Infiltration of bite sites with equine rabies immunoglobulin or human rabies immunoglobulin (HRIG) products is a cornerstone of PEP management along with vaccination. Like vaccines, HRIG supplies are also not guaranteed, especially in travel clinics in LMICs [[11]Jentes ES Blanton JD Johnson KJ Petersen BW Lamias MJ Robertson K et al.The Global Availability of Rabies Immune Globulin and Rabies Vaccine in Clinics Providing Direct Care to Travelers.J Travel Med. 2013; 20: 148-158https://doi.org/10.1111/jtm.12024Crossref PubMed Scopus (36) Google Scholar]. Even when there is access to vaccines and HRIG, the significant time lapse until their administration impairs their efficacy [[11]Jentes ES Blanton JD Johnson KJ Petersen BW Lamias MJ Robertson K et al.The Global Availability of Rabies Immune Globulin and Rabies Vaccine in Clinics Providing Direct Care to Travelers.J Travel Med. 2013; 20: 148-158https://doi.org/10.1111/jtm.12024Crossref PubMed Scopus (36) Google Scholar]. A study from rural Kenya identified that only 5 of 42 healthcare facilities studied had rabies vaccines in their formulary while none had supplies of any type of rabies immunoglobulin [[12]Chuchu VM Kitala PM Bichanga P Ksee D Muturi M Mwatondo A et al.Rabies Elimination in Rural Kenya: Need for Improved Availability of Human Vaccines, Awareness and Knowledge on Rabies and Its Management Among Healthcare Workers.Front Public Health. 2022; 10769898https://doi.org/10.3389/fpubh.2022.769898Crossref Scopus (2) Google Scholar]. Production of monoclonal antibodies, recognized as essential medicines by WHO, may help augment HRIG supplies [[13]Both L Banyard AC van Dolleweerd C Wright E Ma JK Fooks AR Monoclonal antibodies for prophylactic and therapeutic use against viral infections.Vaccine. 2013; 31: 1553-1559https://doi.org/10.1016/j.vaccine.2013.01.025Crossref PubMed Scopus (75) Google Scholar]. Monoclonal antibodies for rabies have emerged as a viable alternative to HRIG, presenting several advantages – the feasibility of large-scale production, enhanced efficacy, reduced side effects, lower costs, and the elimination of animals from the production process. Despite receiving authorization in India in 2016 and the recommendation from the Strategic Advisory Group of Experts (SAGE) of the WHO in 2018, their widespread use is yet to be realized [[14]WHO. Rabies vaccines: WHO position paper.Wkly Epidemiol Rec. 2010; 85: 309-320https://iris.who.int/bitstream/handle/10665/272372/WER9316-201-219.pdf?sequence=1Google Scholar,[15]Kang G Lakhkar A Bhamare C Dharmadhikari A Narwadkar J Kanujia A et al.Active safety surveillance of rabies monoclonal antibody and rabies vaccine in patients with category III potential rabies exposure.Lancet Reg Health Southeast Asia. 2023; 14100207https://doi.org/10.1016/j.lansea.2023.100207Abstract Full Text Full Text PDF Scopus (0) Google Scholar]. In addition to PEP, PrEP in high-risk individuals (occupation or recreational risks) living in highly-endemic countries (incidence rate of dog bites of more than 5%) remains an under-utilized method of prevention of rabies [[16]Lodha L Ananda AM Mani RS. Rabies control in high-burden countries: role of universal pre-exposure immunization.Lancet Reg Health Southeast Asia. 2023; 19100258https://doi.org/10.1016/j.lansea.2023.100258Abstract Full Text Full Text PDF Scopus (1) Google Scholar]. Not only is PrEP a pertinent consideration in canine rabies areas, but also in parts of the Americas where there is a growing concern about exposure to vampire bats [[4]Escobar LE Peterson AT Favi M Yung V Medina-Vogel G. Bat-borne rabies in Latin America.Rev Inst Med Trop Sao Paulo. 2015; 57: 63-72https://doi.org/10.1590/S0036-46652015000100009Crossref PubMed Scopus (45) Google Scholar]. Economic analysis models have demonstrated that a mixed PrEP-PEP prevention strategy is a more cost-effective method versus PEP alone in studies from the Philippines (prevention of 297 deaths over 20 years, savings of USD4.3 million) and India (prevented disability-adjusted life years or DALYs of 451 – 85,069 per million population and USD384 – 352 per DALY averted) [[17]Quiambao B Varghese L Demarteau N Sengson RF Javier J Mukherjee P et al.Health economic assessment of a rabies pre-exposure prophylaxis program compared with post-exposure prophylaxis alone in high-risk age groups in the Philippines.Int J Infect Dis. 2020; 97: 38-46https://doi.org/10.1016/j.ijid.2020.05.062Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar,[18]Royal A John D Bharti O Tanwar R Bhagat DK Padmawati RS et al.A Cost-Effectiveness Analysis of Pre-Exposure Prophylaxis to Avert Rabies Deaths in School-Aged Children in India.Vaccines. 2023; 11: 88https://doi.org/10.3390/vaccines11010088Crossref Scopus (7) Google Scholar]. In light of these findings, there has been advocacy to include rabies PrEP in the national immunization schedules of high burden countries [[16]Lodha L Ananda AM Mani RS. Rabies control in high-burden countries: role of universal pre-exposure immunization.Lancet Reg Health Southeast Asia. 2023; 19100258https://doi.org/10.1016/j.lansea.2023.100258Abstract Full Text Full Text PDF Scopus (1) Google Scholar]. While ensuring access to vaccines and their effective utilization is the most important strategy of RABV infection prevention and control, it is equally imperative to address prevailing detrimental societal norms. A notable example is the reliance on traditional healers for remedies following exposure instead of accessing modern PEP. Moreover, dietary practices, such as the consumption of dog meat associated with unhygienic slaughtering practices, including using bare hands to muzzle dogs' mouths, have been contributors to human rabies cases, as observed in Nigeria and Ghana [19Ekanem EE Eyong KI Philip-Ephraim EE Eyong ME Adams EB Asindi AA. Stray dog trade fueled by dog meat consumption as a risk factor for rabies infection in Calabar, southern Nigeria.Afr Health Sci. 2013; 13: 1170-1173https://doi.org/10.4314/ahs.v13i4.44Crossref Scopus (15) Google Scholar, 20Mshelbwala PP Ogunkoya A Maikai BV. Detection of Rabies Antigen in the Saliva and Brains of Apparently Healthy Dogs Slaughtered for Human Consumption and Its Public Health Implications in Abia State, Nigeria.ISRN Vet Sci. 2013; 468043https://doi.org/10.1155/2013/468043Crossref Google Scholar, 21Tasiame W El-Duah P Johnson SAM Owiredu EW Bleicker T Veith T et al.Rabies virus in slaughtered dogs for meat consumption in Ghana: A potential risk for rabies transmission.Transbound Emerg Dis. 2022; 69: 71-81https://doi.org/10.1111/tbed.14266Crossref Scopus (4) Google Scholar]. Education and strict laws prohibiting the trade of dogs’ meat for dietary consumption are important in shutting down this avenue of RABV transmission, especially considering that countries with such culinary practices also face inadequate PrEP and PEP supplies for rabies prevention [[18]Royal A John D Bharti O Tanwar R Bhagat DK Padmawati RS et al.A Cost-Effectiveness Analysis of Pre-Exposure Prophylaxis to Avert Rabies Deaths in School-Aged Children in India.Vaccines. 2023; 11: 88https://doi.org/10.3390/vaccines11010088Crossref Scopus (7) Google Scholar,[22]Mbilo C Coetzer A Bonfoh B Angot A Bebay C Cassamá B et al.Dog rabies control in West and Central Africa: A review.Acta Tropica. 2021; 224105459https://doi.org/10.1016/j.actatropica.2020.105459Crossref Scopus (29) Google Scholar]. Moreover, several countries in the west and central regions of Africa rely on periodic subsidized mass dog vaccinations in face of the inadequate stocks of human vaccines [[22]Mbilo C Coetzer A Bonfoh B Angot A Bebay C Cassamá B et al.Dog rabies control in West and Central Africa: A review.Acta Tropica. 2021; 224105459https://doi.org/10.1016/j.actatropica.2020.105459Crossref Scopus (29) Google Scholar]. Occurrences of pet dog abandonment post-COVID-19, fueled by concerns about the potential transmission of SARS-CoV-2 by companion animals, were compounded by disruptions in supply chains and the reduction of mass dog vaccination campaigns. The latter experienced a staggering 95% drop in the first year of the pandemic. These events, together with vaccine hesitancy, emerged as significant obstacles, severely impeding public health initiatives against rabies [[23]Nadal D Abela-Ridder B Beeching S Cleaveland S Cronin K Steenson R et al.The impact of the first year of the COVID-19 pandemic on canine rabies control efforts: A mixed-methods study of observations about the present and lessons for the future.Front Trop Dis. 2022; 3866811https://doi.org/10.3389/fitd.2022.866811Crossref Google Scholar,[24]Carroll GA Torjussen A Reeve C. Companion animal adoption and relinquishment during the COVID-19 pandemic: Peri-pandemic pets at greatest risk of relinquishment.Front Vet Sci. 2022; 91017954https://doi.org/10.3389/fvets.2022.1017954Crossref Scopus (7) Google Scholar]. With the world population passing the 8-billion-mark in November 2022 and the corresponding worsening of waste management especially in urban areas, points of contact between humans and free-ranging dogs rise and with it, a higher incidence of rabies [[25]Subedi D Chandran D Subedi S Acharya KP. Ecological and Socioeconomic Factors in the Occurrence of Rabies: A Forgotten Scenario.Infect Dis Rep. 2022; 14: 979-986https://doi.org/10.3390/idr14060097Crossref Scopus (5) Google Scholar]. This is especially notable among south Asian countries where nearly half of annual deaths due to rabies occur [[25]Subedi D Chandran D Subedi S Acharya KP. Ecological and Socioeconomic Factors in the Occurrence of Rabies: A Forgotten Scenario.Infect Dis Rep. 2022; 14: 979-986https://doi.org/10.3390/idr14060097Crossref Scopus (5) Google Scholar]. Enhanced, laboratory-based surveillance programs should be implemented in LMICs to make more accurate diagnoses, initiate timely PEP, understand the true burden of human rabies and to use these data to better inform the public and healthcare practitioners. Public health programs to discourage dietary practices which promote transmission of RABV should be escalated. Studies from West Africa showed that some survey respondents hold the belief that consuming an infected dog's meat will prevent people from acquiring rabies [[25]Subedi D Chandran D Subedi S Acharya KP. Ecological and Socioeconomic Factors in the Occurrence of Rabies: A Forgotten Scenario.Infect Dis Rep. 2022; 14: 979-986https://doi.org/10.3390/idr14060097Crossref Scopus (5) Google Scholar]. Such harmful beliefs should be given due focus beyond the conventional educational programs to achieve clarity of key messages in health education. In recent years, successful awareness programs and mass dog-vaccination programs have reduced the number of human rabies diagnoses by more than half in countries such as Bangladesh – the eighth most populous country in the world and one which had more than 150 deaths due to rabies in 2019 [[26]Ghosh S Rana MS Islam MK Chowdhury S Haider N Kafi MAH et al.Trends and clinico-epidemiological features of human rabies cases in Bangladesh 2006–2018.Sci Rep. 2020; 10: 2410https://doi.org/10.1038/s41598-020-59109-wCrossref PubMed Scopus (23) Google Scholar,[27]Gan H Hou X Wang Y Xu G Huang Z Zhang T et al.Global burden of rabies in 204 countries and territories, from 1990 –2019: results from the global burden of disease study.Int J Infect Dis. 2023; 126: 136-144https://doi.org/10.1016/j.ijid.2022.10.046Abstract Full Text Full Text PDF Scopus (11) Google Scholar]. The uneven distribution in vaccines and HRIG poses significant obstacle to realizing the WHO's ambitious goal of eliminating human deaths from dog-mediated rabies by 2030, often referred as "zero by 30." We need global initiatives that go beyond mere availability and focus on strategies that make rabies vaccines not only accessible but also affordable in resource-limited settings. By tackling this challenge head-on, we can work towards saving lives and mitigating the devastating impact of rabies on communities that are most at risk. After many years of delay, the much-anticipated first steps towards a global roll-out of a three-dose PEP regimen by the Global Alliance for Vaccines and immunization (GAVI) have given light at the end of the tunnel [[28]Nadal D Bote K Abela B. Is there hope to reach the Zero by 30 target for dog-mediated human rabies?.Lancet Glob Health. 2023; 11: 1682-1683https://doi.org/10.1016/S2214-109X(23)00431-XAbstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. 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