A Single Intramuscular Dose of a Plant-Made Virus-Like Particle Vaccine Elicits a Balanced Humoral and Cellular Response and Protects Young and Aged Mice from Influenza H1N1 Virus Challenge despite a Modest/Absent Humoral Response

Abstract

Virus-like-particle (VLP) influenza vaccines can be given intramuscularly (i.m.) or intranasally (i.n.) and may have advantages over split-virion formulations in the elderly. We tested a plant-made VLP vaccine candidate bearing the viral hemagglutinin (HA) delivered either i.m. or i.n. in young and aged mice. Young adult (5-to 8-week-old) and aged (16-to 20-month-old) female BALB/c mice received a single 3-g dose based on the HA (A/California/07/2009 H1N1) content of a plant-made H1-VLP (i.m. or i.n.) split-virion vaccine (i.m.) or were left naive. After vaccination, humoral and splenocyte responses were assessed, and some mice were challenged. Both VLP and split vaccines given i.m. protected 100% of the young animals, but the VLP group lost the least weight and had stronger humoral and cellular responses. Compared to split-vaccine recipients, aged animals vaccinated i.m. with VLP were more likely to survive challenge (80% versus 60%). The lung viral load postchallenge was lowest in the VLP i.m. groups. Mice vaccinated with VLP i.n. had little detectable immune response, but survival was significantly increased. In both age groups, i.m. administration of the H1-VLP vaccine elicited more balanced humoral and cellular responses and provided better protection from homologous challenge than the splitvirion vaccine.KEYWORDS aged-mouse model, influenza, virus-like particles (VLPs), plant-made vaccines A ccording to the World Health Organization, influenza epidemics account for 250,000 to 500,000 deaths worldwide every year (http://www.who.int/mediacentre/factsheets/ fs211/en/). Although vaccines are widely recommended to protect against influenza, the elderly often respond poorly, in part due to prior experience with influenza virus antigens (Ag) (1), but also as a result of immunosenescence (2). The latter affects both innate and adaptive immune responses and has broad implications for both natural infection and vaccination (1, 2).Influenza vaccines for adults are administered by either intramuscular (i.m.) or intradermal injection of detergent-split virions at a fixed dose of 15 g hemagglutinin (HA)/strain (3). These vaccines typically elicit strong antibody responses in healthy young adults and achieve vaccine efficacy (VE) that varies between strains and years but averages 50 to 60% (4). These formulations work less well in the elderly (5

A plant-derived VLP influenza vaccine elicits a balanced immune response even in very old mice with co-morbidities

“…In all of these trials however, subjects with serious comorbid conditions were excluded. These clinical observations are consistent with previous studies showing that healthy BALB/c mice up to 16–20 months of age can be protected from lethal challenge with a single dose of the plant-derived VLP vaccine despite relatively weak (younger animals) or absent (older animals) antibody responses [22]. In the current work, we extended our mouse model to the limit of the murine life-span.…”

“…The development of vaccines that can stimulate cellular responses in addition to antibodies may be of particular interest for this population since older individuals appear to derive significant benefit from cellular memory [3, 21]. We have recently demonstrated that VLP vaccines made in plants that carry HA trimers of either seasonal or pandemic influenza viruses can protect animals (mice, ferrets) in lethal challenge studies despite low and, in some cases, even completely absent antibody responses [22, 23]. After footpad injection in a mouse vaccination model, these VLPs have been shown to move to regional lymph nodes (LN) within minutes where they preferentially associate with antigen-presenting cells (APC) and B cells [24] linked with a rapid increase in LN cellularity and dendritic cell activation [25].…”

“…Although sufficient numbers of animals were not available in the current study to perform a challenge, our previous work with healthy old mice [22] strongly suggests that the pattern of immune response elicited by the VLP vaccine should provide better protection than IIV even in very old mice with multiple co-morbidities. These data also suggest that guarded optimism is appropriate for the outcome of an on-going efficacy study in subjects ≥65 years of age comparing the plant-derived quadrivalent VLP vaccine to a commercial comparator.…”

Plant-derived virus-like particle vaccines drive cross-presentation of influenza A hemagglutinin peptides by human monocyte-derived macrophages

“…10,12,13 These vaccines have been shown to elicit strong and cross-reactive antibody responses against both seasonal and pandemic influenza strains in animal models and human trials. 14–16 They also induce polyfunctional and cross-reactive HA-specific CD4 + T cell responses. 14,15,17 Simultaneous administration of a plant-derived H1-VLP vaccine with ovalbumin (OVA) was recently shown to elicit an OVA-specific CD8 + T cell response in C57BL/6 mice.…”

Induction of protective immune response to intranasal administration of influenza virus‐like particles in a mouse model

“…cell line, which has been proved to be a safe, high-yield, and low-cost vaccine production method (Bright et al, 2008). It has been shown that VLPs, as new vaccine candidates, can be produced with a high yield in a short time period and are also promising platforms to enhance the (Hodgins et al, 2017;Price, Lo, Misplon, & Epstein, 2018;Ren et al, 2018;Trondsen et al, 2015), although other ways, such as the intradermal route, are under investigation . A critical requirement for comparing these routes usually includes a magnitude of stimulated inflammatory as well as protective immune responses.…”