Immunogenicity of an AS01-adjuvanted respiratory syncytial virus prefusion F (RSVPreF3) vaccine in animal models.

Respiratory syncytial virus (RSV) causes a high disease burden in older adults. An effective vaccine for this RSV-primed population may need to boost/elicit robust RSV-neutralizing antibody responses and recall/induce RSV-specific T cell responses. To inform the selection of the vaccine formulation for older adults, RSVPreF3 (RSV fusion glycoprotein engineered to maintain the prefusion conformation) with/without AS01 adjuvant was evaluated in mice and bovine RSV infection-primed cattle. In mice, RSVPreF3/AS01 elicited robust RSV-A/B-specific neutralization titers and RSV F-specific polyfunctional CD4+ T cell responses exceeding those induced by non-adjuvanted RSVPreF3. In primed bovines, RSVPreF3/AS01 tended to induce higher pre-/post-vaccination fold-increases in RSV-A/B-specific neutralization titers relative to non-adjuvanted and Alum-adjuvanted RSVPreF3 formulations, and elicited higher RSV F-specific CD4+ T cell frequencies relative to the non-adjuvanted vaccine. Though AS01 adjuvanticity varied by animal species and priming status, RSVPreF3/AS01 elicited/boosted RSV-A/B-specific neutralization titers and RSV F-specific CD4+ T cell responses in both animal models, which supported its further clinical evaluation as prophylactic candidate vaccine for older adults.

The RSVPreF3-AS01 vaccine elicits broad neutralization of contemporary and antigenically distant respiratory syncytial virus strains.

The RSVPreF3-AS01 vaccine, containing the respiratory syncytial virus (RSV) prefusion F protein and the AS01 adjuvant, was previously shown to boost neutralization responses against historical RSV strains and to be efficacious in preventing RSV-associated lower respiratory tract diseases in older adults. Although RSV F is highly conserved, variation does exist between strains. Here, we characterized variations in the major viral antigenic sites among contemporary RSV sequences when compared with RSVPreF3 and showed that, in older adults, RSVPreF3-AS01 broadly boosts neutralization responses against currently dominant and antigenically distant RSV strains. RSV-neutralizing responses are thought to play a central role in preventing RSV infection. Therefore, the breadth of RSVPreF3-AS01-elicited neutralization responses may contribute to vaccine efficacy against contemporary RSV strains and those that may emerge in the future.

ChAd155-RSV vaccine is immunogenic and efficacious against bovine RSV infection-induced disease in young calves.

Respiratory syncytial virus (RSV) infection causes a substantial lower-respiratory-tract disease burden in infants, constituting a global priority for vaccine development. We evaluated immunogenicity, safety and efficacy of a chimpanzee adenovirus (ChAd)-based vaccine candidate, ChAd155-RSV, in a bovine RSV (bRSV) challenge model. This model closely reproduces the pathogenesis/clinical manifestations of severe pediatric RSV disease. In seronegative calves, ChAd155-RSV elicits robust neutralizing antibody responses against human RSV. Two doses protect calves from clinical symptoms/lung pathological changes, and reduce nasal/lung virus loads after both a short (4-week) and a long (16-week) interval between last immunization and subsequent bRSV challenge. The one-dose regimen confers near-complete or significant protection after short-term or long-term intervals before challenge, respectively. The presence of pre-existing bRSV-antibodies does not affect short-term efficacy of the two-dose regimen. Immunized calves present no clinical signs of enhanced respiratory disease. Collectively, this supports the development of ChAd155-RSV as an RSV vaccine candidate for infants.

Repeated Dose Toxicity Study and Developmental and Reproductive Toxicology Studies of a Respiratory Syncytial Virus Candidate Vaccine in Rabbits and Rats.

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.

Chimeric hemagglutinin supra-seasonal universal influenza vaccine candidates administered sequentially by the intramuscular route are locally and systemically well-tolerated in rabbits.

Sequential intramuscular immunization with chimeric hemagglutinins (cHA) composed of the same conserved HA stalk domain and distinct HA heads is a proposed strategy to produce a supra-seasonal universal influenza vaccine. To evaluate the local tolerance and the local and systemic effects of this strategy, two studies were performed in rabbits. In the first study, two different split virion monovalent cHA vaccines, containing cH5/1N1 and cH8/1N1, with or without AS01 or AS03, were injected at a two-week interval. In the second study, animals were given these vaccines and two weeks later an additional dose of split virion monovalent cHA vaccine containing cH11/1N1, with or without AS01 or AS03. General health status, rectal temperature, local tolerance, ophthalmology, hematology, coagulation, and blood chemistry parameters were monitored. Macroscopic and microscopic evaluations were performed three days after the last dose and after a treatment-free recovery period. The treatment-related changes included body weight loss and food consumption decrease, increases in neutrophil count, C-reactive protein and fibrinogen levels. Microscopic signs of inflammation at the injection sites and immune stimulation of the draining lymph nodes and spleen were also noticed. Most post-injection findings could be linked to the transient inflammation due to the establishment of the desired vaccine-elicited immune response, and were mainly observed in the adjuvanted groups. In conclusion, the sequential administration of different cHA vaccines was locally and systemically well-tolerated in rabbits.

Chimeric Hemagglutinin-Based Influenza Virus Vaccines Induce Protective Stalk-Specific Humoral Immunity and Cellular Responses in Mice.

The high variation of the influenza virus hemagglutinin (HA), particularly of its immunodominant head epitopes, makes it necessary to reformulate seasonal influenza virus vaccines every year. Novel influenza virus vaccines that redirect the immune response toward conserved epitopes of the HA stalk domain should afford broad and durable protection. Sequential immunization with chimeric HAs (cHAs) that express the same conserved HA stalk and distinct exotic HA heads has been shown to elicit high levels of broadly cross-reactive Abs. In the current mouse immunization studies, we tested this strategy using inactivated split virion cHA influenza virus vaccines (IIV) without adjuvant or adjuvanted with AS01 or AS03 to measure the impact of adjuvant on the Ab response. The vaccines elicited high levels of cross-reactive Abs that showed activity in an Ab-dependent, cell-mediated cytotoxicity reporter assay and were protective in a mouse viral challenge model after serum transfer. In addition, T cell responses to adjuvanted IIV were compared with responses to a cHA-expressing live attenuated influenza virus vaccine (LAIV). A strong but transient induction of Ag-specific T cells was observed in the spleens of mice vaccinated with LAIV. Interestingly, IIV also induced T cells, which were successfully recalled upon viral challenge. Groups that received AS01-adjuvanted IIV or LAIV 4 wk before the challenge showed the lowest level of viral replication (i.e., the highest level of protection). These studies provide evidence that broadly cross-reactive Abs elicited by cHA vaccination demonstrate Fc-mediated activity. In addition, cHA vaccination induced Ag-specific cellular responses that can contribute to protection upon infection.