Vaccination of elite athletes against SARS-CoV-2 and broader implications for public health policy

SARS-CoV-2, a human β-coronavirus implicated as thecausative agent in the COVID-19 pandemic, has been the subject of the most globally intensive vaccine development effort inrecorded history. The spectrum of SARS-CoV-2 vaccine candidates, deployedglobally, demonstrates an expansive diversity in regardsto design philosophies and immunological mechanisms of action. In the context of an aging, physically deconditioned, and overweight global population, which finds itself heavily burdened by a high prevalence of non-communicable chronic disease; elite strength, power and endurance athletes represent a minority population comprised of extreme physiological outliers. This report explores the molecular toxicity and pathophysiology of the SARS-CoV-2 spike protein, the design and immunological strategies embodied by the spectrum of SARS-CoV-2 vaccine candidates, and the intersection of these phenomena with the demographic, lifestyle and physiological characteristics of elite athletes; so as to inform vaccination strategies against SARS-CoV-2 which most protect this outlying minority population.

Neuronal delivery of antibodies has therapeutic effects in animal models of botulism

Botulism is caused by a potent neurotoxin that blocks neuromuscular transmission, resulting in death by asphyxiation. Currently, the therapeutic options are limited and there is no antidote. Here, we harness the structural and trafficking properties of an atoxic derivative of botulinum neurotoxin (BoNT) to transport a function-blocking single-domain antibody into the neuronal cytosol where it can inhibit BoNT serotype A (BoNT/A1) molecular toxicity. Post-symptomatic treatment relieved toxic signs of botulism and rescued mice, guinea pigs, and nonhuman primates after lethal BoNT/A1 challenge. These data demonstrate that atoxic BoNT derivatives can be harnessed to deliver therapeutic protein moieties to the neuronal cytoplasm where they bind and neutralize intracellular targets in experimental models. The generalizability of this platform might enable delivery of antibodies and other protein-based therapeutics to previously inaccessible intraneuronal targets.

Special Delivery: Potential Mechanisms of Botulinum Neurotoxin Uptake and Trafficking within Motor Nerve Terminals

Botulinum neurotoxins (BoNTs) are highly potent, neuroparalytic protein toxins that block the release of acetylcholine from motor neurons and autonomic synapses. The unparalleled toxicity of BoNTs results from the highly specific and localized cleavage of presynaptic proteins required for nerve transmission. Currently, the only pharmacotherapy for botulism is prophylaxis with antitoxin, which becomes progressively less effective as symptoms develop. Treatment for symptomatic botulism is limited to supportive care and artificial ventilation until respiratory function spontaneously recovers, which can take weeks or longer. Mechanistic insights into intracellular toxin behavior have progressed significantly since it was shown that toxins exploit synaptic endocytosis for entry into the nerve terminal, but fundamental questions about host-toxin interactions remain unanswered. Chief among these are mechanisms by which BoNT is internalized into neurons and trafficked to sites of molecular toxicity. Elucidating how receptor-bound toxin is internalized and conditions under which the toxin light chain engages with target SNARE proteins is critical for understanding the dynamics of intoxication and identifying novel therapeutics. Here, we discuss the implications of newly discovered modes of synaptic vesicle recycling on BoNT uptake and intraneuronal trafficking.