A Comprehensive Review on Rabies Vaccines for Prevention and Treatment

Abstract

Rabies remains one of the most lethal zoonotic viral infections, causing approximately 59,000 deaths globally each year, with the highest burden concentrated in Asia and Africa [1]. Despite its near-universal fatality rate once clinical symptoms manifest, rabies is entirely preventable through timely administration of post-exposure prophylaxis. This review examines the evolution of rabies vaccine development from Louis Pasteur's pioneering work in 1885 to contemporary biotechnological innovations. We analyze the transition from nerve tissue vaccines to modern cell culture-derived formulations, evaluate current prophylactic protocols including pre-exposure and post-exposure strategies, and explore emerging therapeutic approaches. The review highlights critical advancements in vaccine delivery systems, particularly cost-e ective intradermal vaccination regimens and novel monoclonal antibody alternatives to conventional rabies immunoglobulin. Furthermore, we discuss the global "Zero by 30" initiative aimed at eliminating dog-mediated rabies deaths through integrated One Health strategies. Key challenges including accessibility, a ordability, and equitable distribution are addressed alongside future perspectives on next-generation vaccine technologies and therapeutic interventions.

Keywords

Introduction

Overview of Rabies Disease

Rabies represents an acute, progressive, and invariably fatal viral encephalitis a ecting the central nervous system. Caused by the rabies virus (RABV), a member of the Lyssavirus genus within the Rhabdoviridae family, the disease demonstrates a case fatality rate exceeding 99% in symptomatic individuals[2]. The virus primarily transmits through salivacontaminated bites or scratches from infected animals, with dogs responsible for approximately 99% of human rabies deaths worldwide[3]. This disproportionate burden a ects predominantly poor, rural populations in endemic regions with limited healthcare access, and children comprise approximately half of all fatalities[3].

Historical Milestone: Pasteur's Revolutionary Discovery

The development of rabies prevention marks one of medicine's most signi cant achievements. In 1885, Louis Pasteur, despite su ering from a stroke that had paralyzed his left side, successfully administered the rst rabies vaccine to nine-year-old Joseph Meister, who had been severely bitten 14 times by a rabid dog[4]. Pasteur's methodology involved serial passage of rabies virus through laboratory rabbits to create " xed virus" with predictable seven-day incubation periods, followed by attenuation through air-drying infected rabbit spinal cords under sterile conditions[4]. Over 10 days, Meister received 12 daily injections of progressively virulent vaccine material. The treatment succeeded remarkably—Meister survived and lived to age 64, establishing the foundational principle of post-exposure prophylaxis[4].

By 1890, rabies treatment centers had proliferated globally across Budapest, Madras, Algiers, Florence, São Paulo, Warsaw, Shanghai, and numerous other cities. Pasteur's fundamental contribution—demonstrating that infectious diseases could be prevented through vaccination after exposure—transformed medical practice and established modern immunization principles[5].

Global Epidemiological Burden

Regional Distribution

Current estimates indicate 59,000 annual human rabies deaths across over 150 countries, though substantial underreporting in endemic regions suggests the true burden may be signi cantly higher[1]. Asia bears the highest absolute burden, accounting for 35,172 annual deaths (59.6% of global total), with India alone representing 59.9% of Asian rabies mortality[6]. The annual cost of post-exposure prophylaxis in Asia reaches USD 1.5 billion, representing the highest regional expenditure despite not re ecting proportionate mortality rates[6].

Africa experiences approximately 21,476 annual deaths (36.4% of global total), representing a disproportionate burden relative to population size[3]. Paradoxically, Africa simultaneously spends the least on PEP implementation while experiencing the highest per capita human mortality—a fundamental health equity issue re ecting inadequate access to life-saving interventions[3].

Epidemiological Trends

Global rabies incidence has declined signi cantly from 1990 to 2021, with age-standardized incidence rates falling by 69.4% (from 0.42 to 0.13 per 100,000 population)[1]. Annual case numbers decreased by 54% (from 22,035 to 10,181 cases), with disability-adjusted life years declining 58.4%[1]. These improvements re ect cumulative impacts of dog vaccination programs, enhanced PEP access, and strengthened surveillance systems in high-performing countries.

Nevertheless, persistent disparities remain evident. Contemporary analysis demonstrates the highest age-standardized incidence rates in Nepal (1.71 per 100,000), Ethiopia (1.05), and Malawi (0.77 per 100,000)[1], indicating ongoing challenges related to vaccine accessibility, animal control infrastructure, and healthcare system capacity in speci c regions.

Virus Structure and Pathophysiology

Virological Characteristics

The rabies virus presents as a bullet-shaped enveloped RNA virus measuring 100-300 nm in length and 75 nm in diameter[7]. The virion contains a 12-kilobase, single-stranded negative-sense RNA genome encoding ve essential viral proteins: nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G), and RNA-dependent RNA polymerase (L)[7]. The glycoprotein G forms spike-like trimeric projections on the viral surface, recognizing and binding cellular receptors—making it critical for viral pathogenicity and the primary target for immune response induction[7].

Incubation Period and Clinical Presentation

The incubation period demonstrates remarkable variability, typically ranging from 2-3 months but spanning from as short as 4 days to exceeding one year[8][9]. This variability re ects multiple factors including inoculation site (bites to highly innervated areas like face, head, and neck result in shorter incubation), viral load, wound severity, and host immunocompetence[8]. This prolonged, variable incubation period creates a critical therapeutic window for post-exposure prophylaxis administration before viral penetration of the central nervous system.

Once symptomatic, rabies manifests in two principal clinical forms. Encephalitic rabies (approximately 80% of cases) presents with prodromal symptoms including fever, headache, fatigue, and characteristic focal paresthesias at the bite site, rapidly progressing to encephalitic manifestations including anxiety, agitation, hallucinations, hydrophobia, and autonomic dysfunction[9]. Paralytic rabies (approximately 20% of cases) demonstrates ascending accid paralysis beginning in lower extremities[9]. Regardless of clinical form, the case fatality rate exceeds 99% once symptoms appear, with nearly all symptomatic patients progressing to death within days without intensive life support.

Evolution of Rabies Vaccine Development

First Generation: Nerve Tissue Vaccines

Pasteur's original vaccines and subsequent re nements utilized infected animal nervous tissue, primarily rabbit or sheep spinal cord[10]. Production involved inoculating street (wild-type) rabies virus into rabbit brain tissue, allowing viral replication, and inactivating through sun-drying or chemical treatment with formaldehyde. Despite advantages of low cost and high immunogenicity, nerve tissue vaccines carried signi cant risks including post-vaccinal encephalomyelitis (occurring in 0.01-0.05% of vaccinees), variable potency between batches, and requirement for prolonged daily injections over 14-21 days[10]. These vaccines are now obsolete and no longer recommended by the World Health Organization.

Second Generation: Cell Culture-Derived Vaccines

The development of cell culture technology revolutionized rabies vaccine production, enabling consistent quality and predictable potency.

Human Diploid Cell Vaccine (HDCV)

Developed in 1971 using human diploid cells (MRC-5) as growth substrate, HDCV demonstrates highly consistent immunogenicity with protective antibody titers (≥0.5 IU/mL) achieved in >98% of recipients within 7-10 days[11]. Comparative studies indicate HDCV has lower incidence of adverse reactions compared to other cell culture vaccines while maintaining equivalent seroconversion rates and neutralizing antibody titers[11]. Despite an excellent safety pro le proven over 50+ years of clinical use, high cost (USD 50100 per dose) and cold chain requirements limit accessibility in resource-constrained settings.

Puri ed Vero Cell Vaccine (PVRV)

PVRV utilizes Vero cells (African green monkey kidney cell line) for virus cultivation, followed by inactivation and puri cation. Production costs are substantially lower than HDCV—approximately 40-60% less expensive—due to easier cultivation and more robust scalability[12]. PVRV demonstrates comparable immunogenicity and safety to HDCV and proves e ective for both intramuscular and intradermal administration[12]. The World Health Organization recommends PVRV as an acceptable alternative to HDCV, particularly for PEP programs in endemic regions where cost represents a signi cant constraint.

Puri ed Chick Embryo Cell Vaccine (PCECV)

PCECV employs primary chicken embryo cells as cultivation substrate, with virus inactivation through formaldehyde treatment followed by puri cation. While o ering lower cost than HDCV and proven immunogenicity, preparation of primary chicken embryo cells requires specialized technical expertise and processing infrastructure, resulting in higher labor costs compared to continuous cell lines[13]. Some recipients develop mild allergic reactions to chicken proteins. PCECV remains in use particularly in speci c geographic regions including Japan and European countries where production infrastructure has been established.

Third Generation: Innovative Delivery and Next-GenerationTechnologies

Intradermal Vaccination: A Cost-E ectiveness Breakthrough

Intradermal (ID) vaccination represents a signi cant re nement in vaccine administration, wherein 0.1 mL doses are injected intradermally at speci c sites rather than traditional 1.0 mL intramuscular injections. WHO-recognized ID regimens demonstrate equivalent immunogenicity to IM administration while utilizing approximately 20% of the vaccine volume[10]. Studies con rm that ID vaccination achieves protective neutralizing antibody titers with 4 ID doses (0.1 mL at two anatomical sites each) compared to 5 IM doses (1.0 mL each)[10].

Cost analysis from India demonstrates remarkable economic advantages. A healthcare facility study comparing 1,020 patients receiving IM vaccination in 2015 with 2,256 patients receiving ID vaccination in 2021 revealed ID regimen costs of approximately Rs. 14,18,352 compared to Rs. 35,19,360 for equivalent IM doses—representing 60% cost reduction[11]. Additional analysis found 4,818 dog bite cases vaccinated intradermally cost Rs. 3,90,420 versus approximately Rs. 7,80,570 if administered intramuscularly—a 50% cost reduction[11].

Compliance rates also improved substantially, with 73.04% of patients completing ID regimen compared to only 53.72% completing IM regimen—a 19.32 percentage point improvement re ecting reduced cost burden, fewer clinic visits, and reduced systemic adverse e ects[11].

Recombinant and Genetically-Modi ed Vaccines

Recent molecular biology advances enable development of novel rabies vaccines with enhanced properties. Recombinant Orf virus vector vaccines expressing rabies virus glycoprotein (D1701-V-RabG) demonstrate that single immunization induces high rabies virus-neutralizing antibody titers in multiple species[14]. The Orf virus vector cannot replicate in mammalian cells, reducing safety concerns, and can potentially be administered orally—o ering signi cant logistical advantages for wildlife vaccination programs[14].

Reverse genetics-based approaches have engineered novel rabies viruses with improved characteristics including attenuated live viruses with reduced virulence while maintaining immunogenicity, cytokine-expressing vaccines that enhance innate immune responses, and multi-copy glycoprotein vaccines with duplicated antigen genes increasing antibody responses[15].

Monoclonal Antibody-Based Innovations

Emerging monoclonal antibody (mAb) cocktails represent transformative developments potentially replacing conventional rabies immunoglobulin preparations. A recent clinical study evaluated safety and tolerability of a monoclonal antibody cocktail (docaravimab and miromavimab) in 159 patients with severe animal bites[16]. The cocktail was administered locally to 94.3% of participants, with adverse events occurring in only 10.7% of cases—predominantly mild and localized. Critically, zero rabies cases occurred during six months of follow-up[16].

Monoclonal antibody advantages include consistent standardized potency across batches, elimination of serum sickness and anaphylactic reactions associated with animal-derived immunoglobulins, potential for substantially lower production costs through recombinant DNA technology, possibility of domestic production in endemic regions addressing critical supply chain limitations, potentially longer shelf-life and improved stability facilitating distribution to remote areas, and reduced administration volumes enabling administration by healthcare workers with less specialized training[16].

Post-Exposure Prophylaxis Protocols

Fundamental Principles

Post-exposure prophylaxis consists of three essential components: immediate wound care, administration of rabies immunoglobulin or monoclonal antibodies, and commencement of rabies vaccination[12]. This combined approach demonstrates near-universal e ectiveness (approaching 100% e cacy) when initiated before symptom onset, even after high-risk exposures.

Wound Management Protocols

Initial Treatment

Appropriate wound care represents the critical rst step in PEP, as thorough cleaning removes super cial viral particles and signi cantly reduces infectivity. Recommended protocol includes prolonged vigorous cleansing (at least 15 minutes) with soap and water, application of virucidal agents such as povidone-iodine solution (10% aqueous solution), 70% ethanol, or 2% chlorhexidine, local application of antibiotics (amoxicillin-clavulanate or doxycycline) to prevent secondary bacterial infection, and tetanus prophylaxis if indicated based on vaccination history[12][13].

WHO Exposure Categories

The WHO classi es animal exposures into categories determining PEP necessity and intensity. Category I (touching or feeding animals, licks on intact skin) requires no PEP— only routine wound care. Category II (nibbling of uncovered skin, minor scratches without bleeding) requires PEP with vaccine alone, no immunoglobulin. Category III (transdermal bites or scratches, licks on broken skin, mucosal contamination from saliva) requires full PEP with vaccine plus immunoglobulin[13]. A proposed Category IV addresses severe bites to face, head, and/or neck, or multiple severe bites elsewhere—representing extremely severe exposures meriting highest priority for immunoglobulin in ltration and optimal wound management[17].

Rabies Immunoglobulin Administration

Types and Dosage

Human Rabies Immunoglobulin (HRIG), derived from plasma of hyperimmunized human donors, o ers advantages of human origin, minimal adverse reactions, and consistent quality, but faces limitations of high cost (USD 800-1000 per dose) and limited availability in endemic regions[14]. Recommended dosage is 20 IU/kg body weight, maximum 1500 IU[14].

Equine Rabies Immunoglobulin (ERIG), derived from hyperimmunized horses, provides lower cost (USD 100-200 per dose) and greater global availability, but carries risks of serum sickness (1-2% of recipients) and anaphylactic reactions (0.8-1.6%)[15]. Recommended dosage is 40 IU/kg body weight, maximum 3000 IU[15].

Critical Administration Principles

The fundamental principle of immunoglobulin administration involves in ltration into and around the wound site rather than systemic injection[14]. As much of the calculated dose as anatomically feasible should be in ltrated directly into and around wounds. For localized wounds, dilute immunoglobulin 2-3 fold with sterile 0.9% saline to obtain sucient volume for complete in ltration. For multiple wounds, divide immunoglobulin dose among all wound sites[14].

Timing is critical—immunoglobulin should ideally be in ltrated on the same day as the rst vaccine dose (Day 0), but may be administered up to Day 7 post-exposure[15]. After Day 7, immunoglobulin is not indicated, as vaccine-induced antibody production is presumed to have commenced. Importantly, the total recommended dose must not be exceeded, as studies demonstrate that administering more than twice the recommended dose can suppress antibody response induced by subsequent vaccination, paradoxically reducing protection[15].

Vaccination Schedules

Standard Post-Exposure Vaccination

For individuals without previous rabies vaccination receiving Category III exposure, WHO recommends speci c schedules. The standard intramuscular regimen (Essen Schedule) consists of 1.0 mL doses administered in deltoid (adults) or anterolateral thigh (children) on Days 0, 3, 7, and 14—never in gluteal region[13]. The rst vaccine dose is administered on the same day as wound treatment and immunoglobulin in ltration (Day 0), but in a di erent anatomical site from immunoglobulin in ltration to prevent local neutralization of vaccine virus[13].

The Updated Thai Red Cross intradermal regimen utilizes 0.1 mL × 2 injections at two anatomical sites on Days 0, 3, and 7—totaling 3 doses with 6 injections using substantially less total vaccine volume[12]. This regimen proves particularly valuable in resourceconstrained settings.

Previously Vaccinated Individuals

Individuals who received complete rabies vaccination previously require reduced schedules upon re-exposure. They receive 1.0 mL IM or 0.1 mL × 2 ID doses on Days 0 and 3 only—totaling 2 doses[13][16]. Critically, previously vaccinated individuals do not receive immunoglobulin, as they already possess baseline immunity and immunoglobulin in ltration would be unnecessary and potentially counterproductive[16].

Immunocompromised Patients

Immunocompromised patients require extended 5-dose regimens (Days 0, 3, 7, 14, 28), always receive immunoglobulin regardless of prior vaccination history, and require serological testing to verify adequate response with additional doses if neutralizing antibody titers fall below protective levels (0.5 IU/mL)[13][17]. Immunocompromised populations include HIV/AIDS patients (particularly CD4 counts <200 cells/μL), patients on chronic immunosuppressive therapy, and transplant recipients.

Pre-Exposure Prophylaxis Strategies

Risk Strati cation and Target Populations

Pre-exposure prophylaxis (PrEP) refers to rabies vaccination administered before exposure, intended to "prime" the immune system for more rapid response if subsequent exposure occurs[18]. PrEP is recommended for individuals with occupational or recreational risk of virus exposure.

Continuous Risk Category

Laboratory personnel working with live or concentrated rabies virus require 2 doses on Days 0 and 7, with antibody titer monitoring every 6 months and booster administration if titer falls below 0.5 IU/mL[18].

Frequent Field Risk Category

Personnel with frequent potential exposure to bats, wildlife, or performing animal necropsies—including veterinarians, animal control o          cers, wildlife biologists, and spelunkers—require 3 doses on Days 0, 7, and 21-28, with antibody titer monitoring after initial series and boosters every 3-5 years if occupational exposure continues[18].

Travelers to Endemic Regions

Individuals traveling to regions where rabies is endemic in dogs and medical care access is limited should receive minimum 2 doses on Days 0 and 7, or alternative 3-dose regimen (Days 0, 7, 21-28) for additional protection[19]. PrEP o ers speci c bene ts for travelers: previously vaccinated individuals who receive subsequent exposures require only 2 vaccine doses without rabies immunoglobulin—dramatically reducing cost and logistics; in remote areas where immediate PEP access may be delayed, pre-exposure vaccination provides safety margin; and provides protection against exposures that may go unrecognized[19].

Ecacy and Safety Evidence

Systematic review evidence demonstrates that pre-exposure rabies prophylaxis is safe and immunogenic in both children and adults, including when co-administered with routine childhood vaccines and other concurrent immunizations such as Japanese encephalitis vaccine[20]. Evidence supports that shorter regimens involving fewer doses are safe and immunogenic, and booster intervals can be extended up to 10 years based on serological monitoring[20].

Adverse E ects and Safety Pro les

Local and Systemic Reactions

Common local reactions at injection sites include pain, soreness, swelling, redness, itching, and burning, occurring in 30-50% of recipients depending on route and vaccine type, typically resolving within 2-3 days without intervention[21]. Common systemic reactions include fever (low-grade, typically <38.5°C) in 5-10% of recipients, nausea and vomiting (25%), headache (10-15%), fatigue and malaise (5-10%), and muscle or joint aches (3-8%)[21]. These reactions are generally mild to moderate in severity, self-limited, and resolve within 3-7 days without speci c intervention.

Comparative Vaccine Safety

Meta-analytic comparison demonstrates that HDCV has signi cantly lower incidence of total adverse reactions compared to PCECV, and lower incidence of speci c local adverse reactions (local pain, fever, weakness) compared to PVRV[22]. However, no signi cant di erences are observed in seroconversion rates on Day 7 or rabies virus-neutralizing antibody titers on Day 14, indicating equivalent immunogenicity despite superior safety of HDCV[22].

Serious Adverse Events

True anaphylaxis to rabies vaccine is rare (estimated <1 per 100,000 doses), presenting with urticaria, facial/laryngeal edema, bronchospasm, and hypotension requiring immediate intramuscular epinephrine[21]. Guillain-Barré syndrome has been reported in temporal association with rabies vaccination at estimated rates of 1-2 cases per million vaccinated individuals, though causal relationship remains uncertain[21]. Post-vaccinal encephalitis is exceedingly rare with modern cell culture vaccines (estimated <1 per million doses), contrasting dramatically with nerve tissue vaccines where this complication occurred in 0.01-0.05% of recipients[21].

Serum sickness-like reactions with ERIG, characterized by fever, arthralgia, lymphadenopathy, and rash, occur in 1-2% of recipients, typically 6-14 days postadministration, resolving spontaneously though potentially requiring symptomatic management with analgesics and corticosteroids[15].

Emerging Therapeutic Approaches

Critical Evaluation of the Milwaukee Protocol

The "Milwaukee Protocol" represents the most aggressive experimental approach to symptomatic rabies treatment, emerging from the remarkable 2004 case of Jeanna Giese, who survived rabies without pre-exposure vaccination[23]. The protocol involves therapeutic induced coma, antiviral medications (ribavirin), adjunctive medications (amantadine and ketamine as NMDA receptor antagonists), and intensive critical care support[23].

However, over the past 20 years, the protocol has been applied to approximately 64-70 documented cases worldwide with only 3-5 well-documented survivors[23]. A comprehensive recent review concluded that "over the past 2 decades, no subsequent detailed reports have documented evidence of e cacy," recommending abandonment of the Milwaukee Protocol for symptomatic rabies treatment[23]. The extreme rarity of successful outcomes, combined with high costs and ethical concerns, indicates that aggressive post-symptomatic treatment remains unjusti able when e ective prevention through vaccination exists.

Novel Therapeutic Candidates

F11 Monoclonal Antibody

Uniformed Services University researchers have developed F11, a laboratory-derived monoclonal antibody that e ectively blocks lyssavirus infections in cell culture[24]. Preliminary animal studies in mice using Australian bat lyssavirus and rabies virus strain CVS-11 demonstrated prevention of viral replication when administered at early postinfection stages, maintenance of low viral levels without disease progression, and absence of rabies disease signs over observation periods[24]. While preliminary, this research suggests potential for future therapeutic interventions at very early infection stages, though clinical application remains distant.

Computational Drug Discovery

Recent advances in arti cial intelligence and computational chemistry have identi ed potential small-molecule inhibitors targeting rabies virus proteins. Docking studies suggest compounds with potential antiviral activity including polyethylene glycol 4000 predicted to block RABV glycoprotein receptor binding sites, and natural products (catechins, kaempferol avonoids) showing predicted favorable binding interactions with viral glycoprotein[25]. Drug repurposing approaches have identi ed several existing FDAapproved antiviral agents with predicted activity against rabies proteins including emtricitabine, famciclovir, acyclovir, stavudine, and cidofovir[25]. While computational approaches o er rapid drug identi cation, subsequent in vitro and in vivo validation remains essential before clinical application.

Multi-Epitope Peptide Vaccines

Computational immunoinformatics methods have identi ed B-cell epitopes from rabies virus glycoprotein and nucleoprotein. Multi-epitope constructs engineered to express highly antigenic regions demonstrated 70-80% protective e cacy against virulent rabies challenge in mice[26]. This approach facilitates rapid vaccine redesign based on circulating viral strains, potential for oral mucosal delivery, scalable production in resource-limited settings, and application in wildlife vaccination programs[26].

Global Elimination Strategy: "Zero by 30"

The Global Initiative and One Health Framework

In 2015, the international community established an ambitious goal to eliminate human deaths from dog-mediated rabies by 2030—the "Zero by 30" initiative[27]. This strategy fundamentally embraces the "One Health" framework, recognizing that human rabies elimination requires integrated action addressing human, animal, and environmental health dimensions simultaneously[27].

Key components include universal access to post-exposure prophylaxis and pre-exposure prophylaxis for high-risk populations, mass dog vaccination programs achieving ≥70% coverage in dog populations, oral rabies vaccination programs for wildlife reservoirs, integrated human-animal surveillance systems to detect cases rapidly and trigger response, multisectoral collaboration between human health, veterinary health, animal control, wildlife management, and community sectors, capacity building to strengthen diagnostic capabilities and healthcare infrastructure[27].

Key Strategies and Evidence

Dog Vaccination as Primary Prevention

Dog vaccination represents the single most e ective and cost-e        cient strategy for rabies elimination[28]. Achieving 70% coverage of the dog population creates herd immunity preventing virus circulation in the canine reservoir[28]. Multiple regions have successfully eliminated dog-mediated rabies through sustained dog vaccination programs including Western Europe, Canada, USA, and Japan. In Latin America, 28 of 35 countries report zero human deaths from dog-mediated rabies[28]. Speci c countries demonstrating major progress through integrated strategies combining dog vaccination, improved human PEP access, and community education include Bangladesh, Philippines, Sri Lanka, Tanzania, Vietnam, and South Africa[28].

Improved Access to Post-Exposure Prophylaxis

Challenges in endemic regions include PEP high cost (USD 1.5 billion annually in Asia alone), limited availability of immunoglobulin or high-quality vaccines in rural areas, lack of trained healthcare workers, inadequate cold chain infrastructure, and patient inability to complete multi-visit regimens[6]. Solutions being implemented include introduction of more a ordable intradermal vaccination (60% cost reduction), introduction of PVRV (4050% cost reduction versus HDCV), monoclonal antibody alternatives reducing immunoglobulin costs, task-shifting to community health workers for vaccine administration, and improved cold chain through solar-powered refrigeration[10][11][12].

Surveillance as Foundation for Elimination

E ective surveillance represents a critical component of elimination programs. Research demonstrates that elimination requires surveillance capable of detecting ≥5% (ideally ≥10%) of cases to ensure outbreak response capability[29]. Many endemic countries have surveillance detecting <0.1% of cases, making elimination extremely challenging[29]. Greater intersectoral collaboration between human and animal health surveillance substantially improves detection probability[29]. Community-based rabies surveillance tools integrating bite case management with animal tracking and laboratory investigation have shown promise[30].

Market Preparation and Future Perspectives

Advantages of Modern Rabies Vaccines

Modern rabies vaccines provide strong protection after exposure, particularly when paired with rabies immunoglobulin or monoclonal antibodies, preventing viral progression before central nervous system penetration[12]. Compared to obsolete nerve tissue vaccines, cellculture-based vaccines demonstrate excellent safety with predominantly mild, temporary side e ects suitable for widespread use in children and adults[21]. Current vaccines support antibody levels that can remain strong for extended periods, with newer vaccine platforms aiming for longer immunity with fewer injections[20].

Technological Advancements

Research is advancing toward cutting-edge platforms including recombinant viral vectors, live-attenuated vaccines, virus-like particles, and potentially mRNA approaches that may reduce dosing schedules and enhance rapid protection development[14][15]. Monoclonal antibodies (single or combined cocktails) o er modern alternatives to traditional immunoglobulin—providing consistent quality, easier production, and direct targeting of rabies virus key proteins[16]. Intradermal vaccine regimens utilizing smaller vaccine amounts while o ering equivalent protection make vaccination more a ordable and practical for endemic regions with limited resources[10][11].

Future Research Directions

Vaccine Technology Advancement

Viral vector platforms such as recombinant Orf virus vectors expressing rabies glycoprotein demonstrate promise for single-dose vaccination with high neutralizing antibody responses, with future development potentially enabling oral administration facilitating wildlife vaccination[14]. DNA and mRNA vaccine platforms, proven successful for COVID-19, could enable rapid rabies vaccine development for emerging strains or responses to rabies re-emergence, o ering stability and cost advantages for resourcelimited settings[15]. Broad-spectrum lyssavirus vaccines conferring protection against multiple lyssavirus species beyond RABV could address rising threats of emerging battransmitted lyssavirus infections[15].

Therapeutic Innovation

Continued research into small-molecule antivirals, improved monoclonal antibody cocktails, and early post-exposure therapeutic interventions may eventually expand treatment options beyond prevention[24][25]. Rapid point-of-care rabies diagnostic tests could enable faster case identi cation and response, accelerating elimination timelines[29].

Implementation Science

Understanding barriers to vaccine access, identifying e ective community engagement strategies, and evaluating implementation approaches through rigorous operational research will optimize elimination program e ectiveness. The "Baiyun Model" from Guangzhou, China demonstrates e ective One Health coordination, wherein public health o    cials, hospital clinicians, veterinary services, and community organizations coordinated rapidly following a suspected human rabies case, preventing potential outbreak transmission through integrated multisectoral response[30].

CONCLUSION

Rabies remains a devastating infectious disease causing approximately 59,000 deaths annually, predominantly among disadvantaged populations in Africa and Asia[1]. However, rabies is uniquely distinctive among fatal infectious diseases—it is nearly 100% preventable through timely post-exposure prophylaxis administered before clinical symptom onset[2].

Major ndings of this review demonstrate that Louis Pasteur's development of the rst rabies vaccine in 1885 represented a revolutionary achievement establishing post-exposure immunization principles and launching the modern vaccine development era[4]. Over 135 years of re nement have yielded modern vaccines of exceptional safety and e        cacy. Modern cell culture-derived rabies vaccines (HDCV, PVRV, PCECV) demonstrate >98% seroconversion rates and approach 100% e        cacy when combined with appropriate rabies immunoglobulin and vaccination according to WHO protocols[11][12]. The combination of wound care, immunoglobulin in ltration, and WHO-recommended vaccination schedules is nearly invariably e ective at preventing rabies development when PEP is initiated before symptom onset[12][13].

The disparity between vaccine availability and global distribution represents a fundamental public health inequity. Regions bearing the highest disease burden often have the least PEP access, with cost remaining a critical barrier—PEP costs in Asia estimated at USD 1.5 billion annually[6]. Emerging innovations including monoclonal antibody cocktails, intradermal vaccination, recombinant vaccines, and DNA-based approaches represent transformative developments o ering potential cost reductions, improved accessibility, and enhanced immunogenicity[10][11][14][15][16].

The "Zero by 30" initiative represents an achievable goal through coordinated implementation of proven strategies: universal PEP access, dog vaccination achieving ≥70% coverage, community engagement, improved surveillance, and multisectoral One Health collaboration[27][28]. For pharmacy professionals, maintaining current knowledge of rabies epidemiology, vaccine types, and PEP protocols is essential, alongside counseling patients on appropriate wound care and importance of immediate PEP initiation postexposure, advocating for intradermal vaccination adoption in resource-limited settings, supporting introduction of monoclonal antibody alternatives, and participating in public health initiatives promoting dog vaccination in endemic regions.

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