Generation and characterization of a trackable plant-made influenza H5 virus-like particle (VLP) containing enhanced green fluorescent protein (eGFP)

Young, Katie R.; Arthus-Cartier, Guillaume; Yam, Karen K.; Lavoie, Pierre‐Olivier; Landry, Nathalie; D’Aoust, Marc‐André; Vézina, Louis‐P.; Couture, Manon; Ward, Brian J.

doi:10.1096/fj.15-270421

Cited by 14 publications

(12 citation statements)

References 67 publications

(103 reference statements)

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“…A 1-h temporal difference in the administration of VP6T and NoV VLPs impaired the adjuvant effect dramatically, further supporting the role of rVP6 as a delivery vehicle. It has been published that particulate antigens travel very quickly, in terms of minutes, from the site of injection to the local lymphoid tissue [46]. Although this study does not extend to confirm this, the results suggest that RV VP6 and VLPs may form aggregates when coformulated, VP6 functioning as a carrier.…”

Section: Discussioncontrasting

confidence: 66%

Rotavirus capsid VP6 tubular and spherical nanostructures act as local adjuvants when co-delivered with norovirus VLPs

Malm

Heinimäki

Vesikari

et al. 2017

Clinical and Experimental Immunology

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SummaryA subunit protein vaccine candidate based on norovirus (NoV) virus‐like particles (VLPs) and rotavirus (RV) VP6 protein against acute childhood gastroenteritis has been proposed recently. RV VP6 forms different oligomeric nanostructures, including tubes and spheres when expressed in vitro, which are highly immunogenic in different animal models. We have shown recently that recombinant VP6 nanotubes have an adjuvant effect on immunogenicity of NoV VLPs in mice. In this study, we investigated if the adjuvant effect is dependent upon a VP6 dose or different VP6 structural assemblies. In addition, local and systemic adjuvant effects as well as requirements for antigen co‐delivery and co‐localization were studied. The magnitude and functionality of NoV GII.4‐specific antibodies and T cell responses were tested in mice immunized with GII.4 VLPs alone or different combinations of VLPs and VP6. A VP6 dose‐dependent adjuvant effect on GII.4‐specific antibody responses was observed. The adjuvant effect was found to be strictly dependent upon co‐administration of NoV GII.4 VLPs and VP6 at the same anatomic site and at the same time. However, the adjuvant effect was not dependent on the types of oligomers used, as both nanotubes and nanospheres exerted adjuvant effect on GII.4‐specific antibody generation and, for the first time, T cell immunity. These findings elucidate the mechanisms of VP6 adjuvant effect in vivo and support its use as an adjuvant in a combination NoV and RV vaccine.

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Section: Discussioncontrasting

confidence: 66%

Rotavirus capsid VP6 tubular and spherical nanostructures act as local adjuvants when co-delivered with norovirus VLPs

Malm

Heinimäki

Vesikari

et al. 2017

Clinical and Experimental Immunology

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“…First, they have all of the advantages of nanoparticulate vaccines in terms of antigen protection, presentation and efficient delivery [20, 31]. We have recently shown that plant-derived VLPs bearing influenza H5 injected into the footpad of a mouse can be found in ~10% of the dendritic cells of the draining lymph node in ~10 minutes [32]. They cluster and activate human immune cells through HA-sialic acid interactions to elicit powerful innate responses in human peripheral blood mononuclear cells within minutes in vitro [21].…”

Section: Discussionmentioning

confidence: 99%

Immunogenicity and safety of a quadrivalent plant-derived virus like particle influenza vaccine candidate—Two randomized Phase II clinical trials in 18 to 49 and ≥50 years old adults

et al. 2019

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Background New influenza vaccines eliciting more effective protection are needed, particularly for the elderly who paid a large and disproportional toll of hospitalization and dead during seasonal influenza epidemics. Low (≤15 μg/strain) doses of a new plant-derived virus-like-particle (VLP) vaccine candidate have been shown to induce humoral and cellular responses against both homologous and heterologous strains in healthy adults 18–64 years of age. The two clinical trials reported here addressed the safety and immunogenicity of higher doses (≥15 μg/strain) of quadrivalent VLP candidate vaccine on 18–49 years old and ≥50 years old subjects. We also investigated the impact of alum on the immunogenicity induced by lower doses of the vaccine candidate. Method In the first Phase II trial reported here (NCT02233816), 18–49 year old subjects received 15, 30 or 60 μg/strain of a hemagglutinin-bearing quadrivalent virus-like particle (QVLP) vaccine or placebo. In the second trial (NCT02236052), ≥50 years old subjects received QVLP as above or placebo with additional groups receiving 7.5 or 15 μg/strain with alum. Along with safety recording, the humoral and cell-mediated immune responses were analyzed. Results Local and systemic side-effects were similar to those reported previously. The QVLP vaccine induced significant homologous and heterologous antibody responses at the two higher doses, the addition of alum having little-to-no effect. Serologic outcomes tended to be lower in ≥50 years old subjects previously vaccinated. The candidate vaccine also consistently elicited both homologous and heterologous antigen-specific CD4 + T cells characterized by their production of interferon-gamma (IFN-γ), interleukine-2 (IL-2) and/or tumor-necrosis factor alpha (TNF-α) upon ex vivo antigenic restimulation. Conclusion Overall, the 30 μg dose produced the most consistent humoral and cellular responses in both 18–49 and ≥50 years old subjects, strongly supporting the clinical development of this candidate vaccine. That particular dose was chosen to test in the ongoing Phase III clinical trial.

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“…(27,28) and on the growing body of evidence that the plant-made VLPs stimulate the immune response in a different way than split vaccines. For instance, we have recently shown that these VLPs rapidly access draining lymph nodes (29), where they associate with and activate immune cells, including B cells, macrophages, and dendritic cells (30). Furthermore, these vaccines elicit balanced humoral and cellular responses in both preclinical (young mice and ferrets) and clinical studies in healthy young adults (10)(11)(12)31).…”

Section: Discussionmentioning

confidence: 99%

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

Hodgins

Yam

Winter

et al. 2017

Clin Vaccine Immunol

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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

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Generation and characterization of a trackable plant-made influenza H5 virus-like particle (VLP) containing enhanced green fluorescent protein (eGFP)

Cited by 14 publications

References 67 publications

Rotavirus capsid VP6 tubular and spherical nanostructures act as local adjuvants when co-delivered with norovirus VLPs

Rotavirus capsid VP6 tubular and spherical nanostructures act as local adjuvants when co-delivered with norovirus VLPs

Immunogenicity and safety of a quadrivalent plant-derived virus like particle influenza vaccine candidate—Two randomized Phase II clinical trials in 18 to 49 and ≥50 years old adults

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

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