Efficient oral vaccination by bioengineering virus-like particles with protozoan surface proteins

Abstract

Intestinal and free-living protozoa, such as Giardia lamblia, express a dense coat of variant-specific surface proteins (VSPs) on trophozoites that protects the parasite inside the host’s intestine. Here we show that VSPs not only are resistant to proteolytic digestion and extreme pH and temperatures but also stimulate host innate immune responses in a TLR-4 dependent manner. We show that these properties can be exploited to both protect and adjuvant vaccine antigens for oral administration. Chimeric Virus-like Particles (VLPs) decorated with VSPs and expressing model surface antigens, such as influenza virus hemagglutinin (HA) and neuraminidase (NA), are protected from degradation and activate antigen presenting cells in vitro. Orally administered VSP-pseudotyped VLPs, but not plain VLPs, generate robust immune responses that protect mice from influenza infection and HA-expressing tumors. This versatile vaccine platform has the attributes to meet the ultimate challenge of generating safe, stable and efficient oral vaccines.

Biomaterial Approaches for Understanding and Overcoming Immunological Barriers to Effective Oral Vaccinations

“…[168] A novel bioengineered VLP system utilizing gastrointestinal digestion-resistant surface proteins (VSPs) induced robust activation of systemic and mucosal immune responses upon oral immunization ( Figure 10A). [43] This study observed that the digestion-resistant VSPs as surface proteins were paramount to the efficacy of the platform, as VLPs that did not express VSPs on their surface were less effective in eliciting immunity even when co-delivered with the VSPs (Figure 10B). [43] VSP-coated VLPs vaccines resulted in protection against influenza challenge while oral delivery of the vaccine without the digestion-resistant proteins did not ( Figure 10C).…”

“…[42] Virus-like particles (VLPs) were engineered to express protozoa-derived variant-specific surface proteins (VSPs) to protect VLP surface antigens from gastrointestinal digestion, which are otherwise rapidly degraded in the presence of gastrointestinal extracts. [43] The authors found that cysteine-rich motifs of the VSPs imparted resistance to both gastric and intestinal proteases. [43] Oral vaccination with VSPcoated VLPs generated significantly more serum antibodies and provided protection against viral and tumor challenge compared to uncoated VLPs.…”

“…[43] The authors found that cysteine-rich motifs of the VSPs imparted resistance to both gastric and intestinal proteases. [43] Oral vaccination with VSPcoated VLPs generated significantly more serum antibodies and provided protection against viral and tumor challenge compared to uncoated VLPs. [43] Since the VSPs alone were found to increase production of inflammatory cytokines and expression of stimulatory surface proteins on DCs, it is unknown if the strong immune responses were due to protection from gastrointestinal digestion alone or the immunostimulatory effects of the VSP-coated VLPs.…”

Development of SARS-CoV-2 vaccines: should we focus on mucosal immunity?

“…Moreover, the design of VLPs with improved mucosal immunogenicity can be also achieved by different approaches. For instance, decorating VLPs with variant specific surface proteins from Giardia lamblia has allowed to effectively induce, upon oral administration, immunoprotection against influenza and cancer in murine models [34]. The cases of the nasal influenza vaccine licensed for human use and the development of dried formulations to be administered by noninvasive routes illustrate the potential of mucosal vaccines to surpass the difficulties during their developmental path [35].…”

Engineering a Nanoscale Al‐MOF‐Armored Antigen Carried by a “Trojan Horse”‐Like Platform for Oral Vaccination to Induce Potent and Long‐Lasting Immunity

“…However, most vaccines are known to be fragile and may lose their activities over time if not maintained at the temperature that is recommended by the manufacturer . Moreover, oral vaccination remains problematic because the orally administered vaccine molecules can be readily denatured in gastric acid and degraded by GI proteases, and they encounter biological barriers in the form of tightly packed epithelial cells that line the small intestine …”