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Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infections, and vaccines are needed to treat young children and older adults. One of GSK's candidate vaccines for RSV contains recombinant RSVPreF3 protein maintained in the prefusion conformation. The differences in immune function of young children and older adults potentially require different vaccine approaches. For young children, anti-RSV immunity can be afforded during the first months of life by vaccinating the pregnant mother during the third trimester with unadjuvanted RSVPreF3, which results in protection of the infant due to the transplacental passage of anti-RSV maternal antibodies. For older adults with a waning immune response, the approach is to adjuvant the RSVPreF3 vaccine with AS01 to elicit a more robust immune response. The local and systemic effects of biweekly intramuscular injections of the RSVPreF3 vaccine (unadjuvanted, adjuvanted with AS01, or coadministered with a diphtheria-tetanus-acellular pertussis vaccine) was tested in a repeated dose toxicity study in rabbits. After three intramuscular doses, the only changes observed were those commonly related to a vaccine-elicited inflammatory reaction. Subsequently, the effects of unadjuvanted RSVPreF3 vaccine on female fertility, embryo-fetal, and postnatal development of offspring were evaluated in rats and rabbits. There were no effects on pregnancy, delivery, lactation, or the pre- and postnatal development of offspring. In conclusion, the RSVPreF3 vaccine was well-tolerated locally and systemically and was not associated with any adverse effects on female reproductive function or on the pre- and postnatal growth and development of offspring. [ABSTRACT FROM AUTHOR]

Nephrotoxicity is one of the more common causes of attrition in nonclinical drug development. Like most tissues, the kidney has a limited number of ways of responding to toxicological insults from diverse mechanistic pathways, which can limit the ability to determine mechanisms of renal injury using the assays routinely performed in preclinical toxicologic studies. In situations where the renal injury is unusual in morphology or if a therapeutic margin is low, additional investigative techniques may be needed to identify a potential mechanism of toxicity in order to inform clinical risk assessment or establish human relevance and translatability of the toxicity. While routine microscopic evaluation can suggest a specific pathogenesis, understanding the mechanism of renal injury often requires additional hypothesis-driven investigations and specialized techniques to obtain the data necessary to identify a nephrotoxic mechanism. Nonclinical mechanistic investigations can be resource-intensive and often yield limited new information. Although there are multiple avenues to investigate renal toxicity, no single mechanistic study or prescriptive battery of tests will identify the pathophysiologic basis for every potential mechanism of renal injury. To aid the nonclinical investigator, we outline a tiered approach for prioritizing investigations to provide a rational and linear road map for the exploration of mechanisms of drug-induced kidney injury. Note: This is an opinion article submitted to the Toxicologic Pathology Forum. It represents the views of the authors. It does not constitute an official position of the Society of Toxicologic Pathology, British Society of Toxicological Pathology or European Society of Toxicologic Pathology, and the views expressed might not reflect the best practices recommended by these Societies. This article should not be construed to represent the policies, positions, or opinions of their respective organizations, employers, or regulatory agencies. [ABSTRACT FROM AUTHOR]

The novel self-amplifying mRNA (SAM) technology for vaccines consists of an engineered replication-deficient alphavirus genome encoding an RNA-dependent RNA polymerase and the gene of the target antigen. To validate the concept, the rabies glycoprotein G was chosen as antigen. The delivery system for this vaccine was a cationic nanoemulsion. To characterize the local tolerance, potential systemic toxicity and biodistribution of this vaccine, two nonclinical studies were performed. In the repeated dose toxicity study, the SAM vaccine was administered intramuscularly to rats on four occasions at two-week intervals followed by a four-week recovery period. SAM-related changes consisted of a transient increase in neutrophil count, alpha-2-macroglobulin and fibrinogen levels. Transient aspartate aminotransferase and alanine aminotransferase increases were also noted in females only. At necropsy, observations related to the elicited inflammatory reaction, such as enlargement of the draining lymph nodes were observed that were almost fully reversible by the end of the recovery period. In the biodistribution study, rats received a single intramuscular injection of SAM vaccine and then were followed until Day 60. Rabies RNA was found at the injection sites and in the draining lymph nodes one day after administration, then generally decreased in these tissues but remained detectable up to Day 60. Rabies RNA was also transiently found in blood, lungs, spleen and liver. No microscopic changes in the brain and spinal cord were recorded. In conclusion, these results showed that the rabies SAM vaccine was well-tolerated by the animals and supported the clinical development program. • Self-amplifying mRNA (SAM) is a novel platform technology for vaccines. • Biodistribution and potential local and systemic effects of a rabies SAM vaccine were assessed in rats. • All findings could be linked to the vaccine-elicited immune response. • Rabies RNA was found mainly at the injection site and draining lymph nodes. • The administration of the rabies SAM vaccine was locally and systemically well-tolerated. [ABSTRACT FROM AUTHOR]