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Current Projects in the Morrison Laboratory

Project 1: Conformational forms of viral proteins for stimulation of protective responses.

Respiratory syncytial virus (RSV) is a substantial threat to human health most severely affecting infants, young children, and the elderly. However, no licensed RSV vaccine exists although numerous candidates have been characterized in preclinical and clinical studies spanning five decades. This failure is due in large part to a lack of understanding of some fundamental issues related to immune responses to RSV. Our goal is to determine how F protein structure can be manipulated to overcome this failure to stimulate high titers of protective antibodies as well as long-term protective immunity. We have developed virus-like particles (VLPs) containing RSV F and G glycoproteins and demonstrated that they have significant potential as reagents to characterize immune responses to different conformational forms of these proteins. We have shown that the form of the F protein plays a major role in induction of high titers of anti-F protein neutralizing antibody responses in naïve animals. Surprisingly, we have found that the form of F protein also significantly impacts responses in animals previously infected with RSV. These new results lead us to test the hypothesis that the conformation of the RSV F protein impacts, in previously infected animals, stimulation of specific memory B cells and thus levels of protective antibodies.

Project 2: Maternal immunization for protection of offspring from RSV disease.

RSV, a paramyxovirus, is the single most important cause of acute respiratory tract infections in infants and young children. It is estimated that, worldwide, there are annually 33.8 million RSV infections with ten percent requiring hospitalization and up to 200,000 deaths. In the US, there are annually up to 144,000 hospitalizations. These infections are particularly serious for premature infants and infants with underlying health issues as these children are at significant risk for potentially life-threatening infections that require hospitalization and intensive care. It has also been documented that infants with severe RSV infections are at significantly increased risk for developing asthma in later years. RSV infections have a particularly significant impact on the health and survival of infants and young children in the developing world. There is no licensed RSV vaccine even for older children or adults. Indeed, vaccination of neonates is likely ineffective due to the immaturity of their immune system. In addition, neonate immunization is potentially unsafe. A safer more effective way to protect newborns by vaccination is to ensure transfer to neonates of effective concentrations of maternal neutralizing antibodies after maternal immunization. Immunizing mothers is, however, complicated by the fact that most adults have experienced multiple RSV infections and have low levels of anti-RSV antibodies, antibodies that are clearly not protective. Previous attempts to increase levels of protective antibodies by vaccination of mothers with different vaccine candidates have not been successful. It is our hypothesis that immunization of mothers during pregnancy with VLPs containing the pre-fusion conformation of the RSV F protein will significantly boost their serum neutralizing antibodies responses, even in mothers with a past history of RSV infection. Using cotton rats as surrogates for human populations, we are evaluating the role of preexisting immunity in induction of neutralizing antibodies by pre-F VLP Immunization, the transfer of maternal anti-RSV antibodies to neonates, protection of offspring of immunized moms from RSV challenge, and the potential for enhanced pathology in RSV infected offspring of immunized mothers.

Project-3: RSV vaccine candidates for the elderly.

Respiratory syncytial virus (RSV) is a significant threat to elderly populations, a threat that rivals that of influenza virus. Currently it is estimated that RSV infections in the elderly result in 11,000 to 17,000 deaths per year in the US alone and ten times that number of RSV associated hospitalizations. The world-wide population over age 60 is predicted to reach 2.1 billion, more than 20% of the total population, by 2050. In some developed countries, this percentage is already at 20-25%. Such an expansion of this population over the next few decades will pose a greatly increased public health burden making development of RSV vaccines for the elderly an important priority. However, attempts to develop effective RSV vaccines, which have proceeded since the late 1960s, have failed. This problem is compounded by the requirement that an RSV vaccine for the elderly must overcome immune senescence that accompanies aging. This project is developing novel virus-like particles (VLPs) as an RSV vaccine for elderly populations. These VLPs contain the RSV pre-fusion F protein and the RSV G protein. They have been shown to be an effective vaccine in mice and cotton rats (CRs). In recent studies, we have defined effects of prior RSV infection on immune responses to pre-fusion F VLP immunization and reported results consistent with our novel conclusion that RSV infection can induce healthy RSV memory responses, however, a second RSV infection cannot activate this memory, a result consistent with the inability of RSV infections of humans to protect from subsequent RSV infections. Strikingly, however, a single immunization with a pre-fusion F containing VLP can robustly activate memory established by prior RSV infections resulting in high titer neutralizing antibodies with high avidity and robust levels of F protein specific splenic memory B cells and bone marrow associated plasma cells (LLPC) while a second RSV infection cannot. These observations suggest that the challenge for a vaccine for the elderly, who have experienced RSV infections multiple times, is to efficiently recall this memory. This proposal is based on the hypothesis that pre-fusion F containing VLPs can accomplish this recall. This project is exploring different ways to optimize activation of memory responses to RSV.

Project 4: Immune responses to different forms of SARS-CoV-2 S protein.

The goal of this project is to identify the optimal conformational form of the SARS-CoV2 S protein for induction of protective responses. We are employing the approaches we have developed for generation of vaccine candidates for respiratory syncytial virus (RSV). The attachment protein for SARS-CoV-2 is the S protein, which binds to the ACE-2 cell receptor and is the primary target for vaccine development. Our focus is on immune responses to VLPs assembled with different versions of the SARS-CoV-2 S protein. This project is proceeding by assembling and validating of VLPs with different conformations of the S protein or a subset of S protein sequences, immunization of mice with the VLPs in order to characterize of the antibody responses and durability of protective responses to different S protein sequences, and assessment of the safety of the immunization.