Page 21 - IMO-2-3

Innovative Medicines & Omics Progress in antivenom therapy

Shortly thereafter, significant advancements were made with heterologous proteins. These challenges laid the
in South America by Brazilian physician, immunologist, groundwork for 21 -century calls to modernize and
st
and biomedical scientist Vital Brazil Mineiro da Campanha. innovate antivenom therapeutics through biotechnological
Recognizing that the venoms of different snake species and recombinant approaches.
required targeted therapeutic strategies, Vital Brazil In sum, the historical trajectory of antivenom therapy
expanded on Calmette’s work by developing polyvalent is a compelling example of translational medical science
antivenoms—preparations capable of neutralizing the that spans over a century. The foundational contributions
venoms of multiple species, especially those endemic to of Calmette and Vital Brazil not only saved countless
Brazil, such as Bothrops, Crotalus, and Micrurus. Unlike lives but also galvanized international efforts to confront
7
Calmette, who initially produced monovalent antivenoms, one of the most lethal yet neglected causes of injury and
Vital Brazil’s research highlighted the antigenic specificity mortality in the Global South. Their legacy continues to
of venom components and the need for regionally adapted shape contemporary research, underscoring the enduring
treatments. His meticulous experiments demonstrated that importance of venom immunology as both a clinical and
snake venoms were not universally interchangeable, even scientific frontier.
among species within the same family, and that effective
antivenom production required immunization with locally 3. Present state of antivenom therapy
relevant venom mixtures. These innovations culminated in
the establishment of the Instituto Butantan in São Paulo in Modern antivenom production is fundamentally grounded
1901, a premier institution that has since become one of in immunological principles established over a century ago
the world’s leading centers for venom research, antivenom by Calmette and Vital Brazil, yet the process has undergone
production, and public health outreach. 8 considerable refinement to improve yield, purity, and
safety. The most common production method involves
The early 20 century witnessed further expansion hyperimmunization of large, domesticated animals—most
th
of antivenom research in other parts of the world. In often horses (Equus ferus caballus) or sheep (Ovis aries)—
Australia, systematic efforts were initiated to combat the through the administration of gradually escalating doses
medically significant elapids, particularly Pseudonaja of snake venom. These animals develop a robust humoral
(brown snakes) and Oxyuranus (taipans), leading to the immune response, generating high titers of polyclonal IgG
foundation of the Commonwealth Serum Laboratories antibodies capable of neutralizing the toxic components of
in 1916. Similarly, India and Africa developed region- the venom.
9
specific immunization protocols to address the “Big Four” After sufficient antibody production is confirmed
snakes in South Asia and medically important vipers in through serological assays, blood is harvested from
Africa, respectively. These global initiatives contributed to the animals, and plasma is separated for downstream
the creation of a foundational infrastructure for snakebite processing. The resulting antibody preparations are
management, with the shared understanding that regional subjected to fractionation and enzymatic digestion to
ecological diversity required tailored immunobiological enhance their pharmacological profiles and minimize
strategies.
adverse reactions. Three principal antivenom formulations
Throughout much of the 20 century, antivenom are commonly used: Whole IgG; F(ab’) fragments,
th
2
therapy remained grounded in the principles established by produced through pepsin digestion (which removes the Fc
Calmette and Vital Brazil, namely, passive immunization portion while preserving bivalent antigen-binding sites);
using animal-derived polyclonal antibodies. Horses (and and Fab fragments, derived through papain digestion
occasionally sheep) were the preferred source animals (monovalent and rapidly cleared from circulation). The
due to their size, immunologic tolerance, and capacity choice of fragment type influences both the efficacy and
to generate high antibody titers. The antibodies were safety of the antivenom. While Fab fragments exhibit faster
often administered as whole immunoglobulin G (IgG) tissue penetration and reduced immunogenicity, they are
molecules, though subsequent innovations led to the also associated with shorter half-lives and an increased risk
enzymatic digestion of IgG into smaller fragments, such of venom recurrence, or “rebound” toxicity, particularly in
as F(ab’)₂ and Fab, to reduce the incidence of adverse envenomations involving tissue-depositing toxins.
immunologic reactions and improve pharmacokinetics.
Despite their proven life-saving capabilities, traditional
Despite its life-saving potential, traditional antivenoms suffer from multiple limitations that impede
antivenom therapy has been historically hindered by their effectiveness and availability in real-world clinical
limitations in production scalability, quality control, settings. One of the most prominent challenges is venom
geographic specificity, and adverse reactions associated specificity. Because antivenoms are typically raised against

Volume 2 Issue 3 (2025) 15 doi: 10.36922/IMO025240026