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SARS-CoV-2 new waves are primarily caused by changes to the spike protein (S), which can substantially decrease the efficacy of vaccines. Therefore, we tested several multivalent mRNA-LNP vaccines, targeting the full-length S proteins of different variants, and identified an optimal combination for protection against VOCs in BALB/c mice. The tested formulations included trivalent (WT + BA.5 + XBB.1.5), pentavalent (WT + BA.5 + XBB.1.5 + BQ.1.1 + CH.1.1), and octavalent (WT + BA.5 + XBB.1.5 + BQ.1.1 + CH.1.1 + Alpha + Delta + BA.2) vaccines. Among these multivalent vaccines, the pentavalent vaccine showed superior protection for almost all tested variants. Despite this, each multivalent vaccine elicited greater broad-spectrum neutralizing antibodies than the previously evaluated bivalent vaccine (WT + BA.5). Subsequently, we redesigned the multivalent vaccine to efficiently generate neutralizing antibodies against recent VOCs, including EG.5.1. Immunization with the redesigned pentavalent vaccine (WT + EG.5.1 + XBB.1.16 + Delta + BA.5) showed moderate levels of protection against recent Omicron VOCs. Results suggest that the neutralization activity of multivalent vaccines is better than those of the tested bivalent vaccines against WT + BA.5 and WT + EG.5.1. Moreover, the pentavalent vaccine we developed may be highly useful for neutralizing new Omicron VOCs.

RESUMEN

Background. Intermittent hypoxia can induce respiratory neuroplasticity to enhance respiratory motor outputs following hypoxic treatment. This type of respiratory neuroplasticity is primarily mediated by the activation of Gq-protein-coupled 5-HT2 receptors and constrained by Gs-protein-coupled 5-HT7 receptors. Objective. The present study hypothesized that the blockade of 5-HT7 receptors can potentiate the effect of intermittent hypercapnic-hypoxia on respiratory function after cervical spinal cord contusion injury. Methods. The ventilatory behaviors of unanesthetized rats with midcervical spinal cord contusions were measured before, during, and after daily acute intermittent hypercapnic-hypoxia (10 episodes of 5 minutes of hypoxia [10% O2, 4% CO2, 86% N2] with 5 minutes of normoxia intervals for 5 days) at 8 weeks postinjury. On a daily basis, 5 minutes before intermittent hypercapnic-hypoxia, rats received either a 5-HT7 receptor antagonist (SB269970, 4 mg/kg, intraperitoneal) or a vehicle (dimethyl sulfoxide). Results. Treatment with intermittent hypercapnic-hypoxia induced a similar increase in tidal volume between rats that received SB269970 and those that received dimethyl sulfoxide within 60 minutes post-hypoxia on the first day. However, after 2 to 3 days of daily acute intermittent hypercapnic-hypoxia, the baseline tidal volumes of rats treated with SB269970 increased significantly. Conclusions. These results suggest that inhibiting the 5-HT7 receptor can transiently improve daily intermittent hypercapnic-hypoxia-induced tidal volume increase in midcervical spinal contused animals. Therefore, combining pharmacological treatment with rehabilitative intermittent hypercapnic-hypoxia training may be an effective strategy for synergistically enhancing respiratory neuroplasticity to improve respiratory function following chronic cervical spinal cord injury.

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RESUMEN

The present study was designed to evaluate the therapeutic effectiveness and mechanism of acute intermittent hypoxia on respiratory function at distinct injury stages following mid-cervical spinal contusion. In the first experiment, adult male rats received laminectomy or unilateral contusion at 3rd-4th cervical spinal cord at 9 weeks of age. The ventilatory behavior in response to mild acute intermittent hypercapnic-hypoxia (10 episodes of 5 min of hypoxia [10% O2, 4% CO2, 86% N2] with 5 min of normoxia intervals) was measured by whole-body plethysmography at the acute (∼3 days), subchronic (∼2 weeks), and chronic (∼8 weeks) injury stages. The minute ventilation of contused animals is significantly enhanced following acute intermittent hypercapnic-hypoxia due to an augmentation of the tidal volume at all time-points post-injury. However, acute intermittent hypercapnia-hypoxia-induced ventilatory long-term facilitation was only observed in uninjured animals at the acute stage. During the second experiment, the effect of acute intermittent hypercapnic-hypoxia on respiration was examined in contused animals after a blockade of serotonin receptors, or adenosine 2A receptors. The results demonstrated that acute intermittent hypercapnic-hypoxia-induced enhancement of minute ventilation was attenuated by a serotonin receptor antagonist (methysergide) but enhanced by an adenosine 2A receptor antagonist (KW6002) at the subchronic and chronic injury stages. These results suggested that acute intermittent hypercapnic-hypoxia can induce respiratory recovery from acute to chronic injury stages. The therapeutic effectiveness of intermittent hypercapnic-hypoxia is dampened by the inhibition of serotonin receptors, but a blockade of adenosine 2A receptors enhanced respiratory recovery induced by intermittent hypercapnic-hypoxia.

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