UConn researcher Paulo Verardi, associate professor of pathobiology and veterinary science in the College of Agriculture, Health and Natural Resources, has demonstrated the success of a vaccine against Zika virus and recently published his findings in Scientific Reports, a Nature Research publication.
He has also filed provisional patents with UConn’s Technology Commercialization Services for the novel vaccine platform technology used to generate the vaccine, as well as genetic modifications made to the vaccine that significantly enhance expression of the vaccine antigen.
Verardi, a Brazilian native, was in Brazil visiting family in the summer of 2015 when the Zika outbreak first began to make waves and soon reached epidemic status.
Back in the United States, Verardi kept tabs on the Zika epidemic and its emerging connection to microcephaly, a serious birth defect that causes babies to be born with small heads and underdeveloped brains.
In October of that year, Verardi called then-Ph.D.-student Brittany Jasperse (CAHNR ’19) into his office and told her he wanted to apply their newly developed vaccine platform and start developing a vaccine for Zika virus.
Verardi and Jasperse quickly obtained funding through the Office of the Vice President for Research’s Research Excellence Program to generate preliminary data that was then used to secure funding from the National Institutes of Health (NIH).
Verardi and Jasperse were among the first researchers in the US to receive NIH funding to generate a vaccine against Zika virus, thanks to Verardi recognizing the significance of Zika virus early.
Modern advancements in genomic technology have expediated the vaccine development process. In the past, researchers needed to have access to the actual virus. Now just obtaining the genetic sequence of the virus can be sufficient to develop a vaccine, as was the case for the Zika vaccine Verardi and Jasperse developed, and the COVID-19 vaccines currently approved for emergency use in the United States and abroad.
Using the genetic sequence of Zika virus, Verardi and Jasperse developed and tested multiple vaccine candidates that would create virus-like particles (VLPs). VLPs are an appealing vaccine approach because they resemble native virus particles to the immune system and therefore trigger the immune system to mount a defense comparable to a natural infection. Critically, VLPs lack genetic material and are unable to replicate.
The vaccine Verardi and Jasperse developed is based on a viral vector, vaccinia virus, which they modified to express a portion of Zika virus’ genetic sequence to produce Zika VLPs. Their vaccine has an added safety feature that it is replication-defective when given as a vaccine but replicates normally in cell culture in the lab.
“Essentially, we have included an on/off switch,” Jasperse says. “We can turn the viral vector on in the lab when we’re producing it by simply adding a chemical inducer, and we can turn it off when it’s being delivered as a vaccine to enhance safety.”
The team developed five vaccine candidates in the lab with different mutations in a genetic sequence that acts as a signal to secrete proteins. They evaluated how these mutations affected the expression and formation of Zika VLPs and then selected the vaccine candidate that had the highest expression of VLPs to test in a mouse model of Zika virus pathogenesis. This model was developed by Helen Lazear of University of North Carolina at Chapel Hill, whose lab Jasperse now works in as a postdoctoral research associate.
Verardi and Jasperse found that mice who received just a single dose of the vaccine mounted a strong immune response and were completely protected from Zika virus infection. They did not find any evidence of Zika virus in the blood of challenged mice who were exposed to the virus after vaccination.
Zika virus is part of a group of viruses known as flaviviruses which include dengue virus, yellow fever virus, and West Nile virus. Verardi and Jasperse’s findings, particularly the mutations they identified that enhanced expression of Zika VLPs, could be useful for improving production of vaccines against diseases caused by other related flaviviruses.
Ongoing work in the Verardi lab incorporates these novel mutations into vaccine candidates against other viruses, including Powassan virus, a tick-borne flavivirus that can cause fatal encephalitis.
Verardi emphasizes that developing vaccines for viruses, in this case Zika, help the world be better prepared for outbreaks of novel and emerging viruses by having vaccine development frameworks in place.
“Emerging viruses are not going to stop popping up any time soon, so we need to be prepared,” Verardi says. “Part of being prepared is to continue the development of these platforms.”
Zika virus (ZIKV) is a recently re-emerged viral pathogen that is associated with severe neurological diseases, including Guillain-Barré Syndrome (GBS) and congenital Zika virus syndrome (CZS) (1). In order to prevent the consequences of such infections, a variety of ZIKV vaccines have been developed and evaluated in experimental animal models (2), though none has been licensed to date.
Some groups of investigators have focused on the ZIKV E protein as an immunogen. ZIKV E is an envelope glycoprotein that is major protein responsible for the induction of protective immunity (3, 4). This is a transmembrane protein with three extracellular domains (DI, DII, and DIII), in which DIII has been shown to induce the most potent neutralizing activity against ZIKV, without inducing undesirable antibody-dependent enhancement (ADE) (4).
The use of recombinant protein antigens is reported as less reactogenic than whole inactivated pathogens; furthermore, recombinant proteins provide a number of advantages for production, compared to the inactivated pathogen, particularly in terms of safety and ease of scalability.
However, recombinant-based vaccines usually require adjuvants. Adjuvants are added to vaccines either to stimulate innate immunity or to boost adaptive immune responses to antigens, ensuring efficient trafficking of effector and memory B and T cells (5, 6), thus improving cell-mediated immune responses (7–9).
Despite many decades of development, a very small number of adjuvants are currently approved for use in human vaccines (6). Currently, nanotechnology is being employed in response to the need for new adjuvant and delivery systems that can increase cellular and humoral immune responses.
The use of nanoadjuvants in vaccine formulations allows enhanced immunogenicity and antigen stability, as well as targeted delivery and slow release (10). In this context, one group of adjuvants, the saponin-based adjuvants (SBA), has been proposed as an alternative to classical adjuvants for the design of new vaccines due to the ability of these compounds to trigger Th1 responses (9, 11–13).
Recently, two vaccines that employ recombinant proteins as antigens were licensed for human use; one is a vaccine against herpes zoster (Shingrix™); another is against malaria (Mosquirix™). Both vaccine formulations contain QS-21, a saponin from Quillaja saponaria, as an adjuvant (8).
One critical issue concerning the use of saponins as vaccine adjuvants is their toxicity (14). For this reason, nanoadjuvants, such as immmunostimulating complexes or ISCOMs, have been formulated due to their reduced toxicities (8, 13, 15). Our research group previously reported that nanoadjuvants from Q. brasiliensis saponins are safe adjuvants in preclinical experiments (16).
Furthermore, these nanoparticles are efficiently internalized by dendritic cells, promote high antibody titers, enhance delayed-type hypersensitivity (DTH) responses and stimulate the proliferation of Th1 lymphocyte subsets (17). Moreover, these nanoadjuvants, in the absence of antigen (ISCOM-matrices), generate a local and transient immunocompetent environment, with overexpression of cytokine and chemokine genes related to inflammation (18).
Notably, the recombinant spike protein antigen, recently recovered from SARS-CoV-2, was formulated with a Q. saponaria saponin-based nanoadjuvant (Matrix-M). This putative vaccine is currently in phase 1/2 clinical trials as a possible candidate for fighting the SARS-CoV-2 pandemic (19, 20).
In this study, an experimental vaccine was prepared using a recombinant ZIKV E domain III (zEDIII) antigen. The zEDIII was obtained using an Escherichia coli and used as an immunogen in a nanoadjuvanted formulation (ISCOMs with the Q. brasiliensis saponins, IQB80). The nanoadjuvant-based vaccine formulation was tested in mice and its immunogenicity was evaluated in comparison to an equivalent vaccine preparation that was adjuvanted with alum, a standard adjuvant used in vaccines for humans.
reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969523/
More information: Brittany Jasperse et al. Single dose of a replication-defective vaccinia virus expressing Zika virus-like particles is protective in mice, Scientific Reports (2021). DOI: 10.1038/s41598-021-85951-7