A plant-based influenza vaccine?

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Seasonal influenza remains a serious threat to human health despite the availability of vaccines. Vaccines in use have some limitations, so plant-derived production could potentially overcome these. Now, for the first time, researchers are investigating the efficacy of a plant-derived quadrivalent influenza vaccine in randomized phase 3 trials.

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Nicotiana benthamiana:

The plant Nicotiana benthamiana (also called "benth") belongs to the tobacco species and is native to Australia. Since a large number of different plant viruses can successfully infect N. benth, it is one of the most widely used experimental hosts in plant virology. Furthermore, this tobacco species is susceptible to a wide range of other plant pathogens such as bacteria or fungi, making this species a mainstay in host-pathogen research - especially in the context of innate immunity and defense signaling. Although N. benth acts as an important research model, relatively little is known about the origin, genetic variation, or ecology of the plant species currently used in studies.

Currently, biotechnology company Medicago Inc. is using this tobacco species to produce virus-like particles over short incubation times and in large quantities, enabling more efficient manufacturing production for a potential COVID-19 vaccine. A Phase I clinical trial was initiated in July 2020 for this purpose.

Also, the medical journal The Lancet published two randomized Phase 3 trials in October 2020 that used N. benth to generate quadrivalent influenza vaccines from it. Because the virus changes every year, recommendations for vaccine production regarding one or more strains change. As reference strains, common trivalent vaccines include two influenza A viruses and one influenza B virus - quadrivalent vaccines include a second influenza B virus. Plants used for this purpose were transfected(i.e., introduction of foreign DNA or RNA into specific cells) with an attenuated soil bacterium, Agrobacterium tumefaciens, which "expressed" a specific protein of the influenza A virus (hemagglutinin) in the DNA. The vaccine was obtained from the transfected plants in the form of virus-like particles.

Normally, treatment of influenza is by bed rest and only symptomatic with pain and fever medications such as ibuprofen oracetaminophen .

Herbal Study Method:

This involved two randomized, multinational, blind studies conducted in the northern hemisphere during the 2017-2018 and 2018-2019 influenza seasons. The first study examined participants aged 18-64 years at 73 different sites (Brief: Study 1) - the second looked at those aged 65 years and older at 104 sites in Asia, Europe and North America (Brief: Study 2). Inclusion criteria for Study 1 were BMI (i.e. body mass index) of less than 40 kg/m2, appropriate age at baseline, and generally positive health. For study 2, the criteria were: BMI of 35 kg/m2 or less, the appropriate age at study entry, not residing in a rehabilitation center or nursing home, and no acute medical problems.

Participants in Study 1 were randomized to receive either a so-called QVLP vaccine (i.e., quadrivalent virus-like particle) with a dose of 30 μg hemagglutinin per strain, or placebo.

Study 2 participants received the same dose of QVLP vaccine or quadrivalent inactivated vaccine (short: QIV with 15 μg hemagglutinin per strain).

Here, the primary objective in Study 1 was the absolute efficacy of the vaccine in preventing clinically diagnosed respiratory disease caused by influenza strains. The primary objective in Study 2 was the relative efficacy of the vaccine to prevent clinically-confirmed influenza-like illness caused by any influenza strain.

Results Study 1:

In the first, placebo-controlled, randomized trial, a total of 10 160 adults were studied. Of these, 40% were men (n=4051) and 60% were women (n=6085) - the mean age was 44.6 years. In this study, the herbal vaccine was a so-called immunogen (i.e. antigen that can trigger an immune response in the body). Since the absolute efficacy of the vaccine in preventing respiratory disease was 35.1%, the primary end goal of 70% efficacy was not achieved. In comparison, the efficacy of the influenza vaccine for the 2017/18 season in the UK was 15% - it should be noted that a key influenza A strain (H3N2) was shown to have low efficacy.

Results Study 2:

The second study compared the plant-derived vaccine with a chicken egg-derived quadrivalent inactivated vaccine in 12 794 older adults. This included 44.1% men (n=5605) and 55.9% women (n=7113) - the mean age was 72.2 years. The plant-based vaccine had a relative effectiveness of 8.8% in preventing influenza-like illness compared to the "animal-based" vaccine. Although the plant vaccine was able to show similar protective results, it achieved a lower antibody response.

Why do we need influenza vaccines from plants?

An unresolved issue to date is a patchy match between vaccine and circulating influenza strains - particularly influenza A (H3N2) strains. These strains can infect the human body with increasing efficiency, which becomes problematic when this virus is cultured in chicken eggs for a vaccine. During virus cultivation in eggs, this can adapt to better bind to cell receptors on chicken cells. This change in culturing allows the egg-derived hemagglutinin to differ from the hemagglutinin "voiced" by the globally circulating H3N2 virus. As a result, antibodies produced against this strain of the virus are less able to neutralize it. Alternative production methods could provide solutions - so far, two alternative approaches have been licensed: the use of insect cells to produce a recombinant protein (i.e. using genetic engineering methods, the protein can reassemble in the body) and mammalian cell lines to grow viruses (i.e. cells of a tissue type that can reproduce indefinitely).


Since, according to research published in the scientific journal PLOS Pathogens in 2020, the H3N2 strain was found to be able to fight the immune response in the human body more easily through a mutation than before, an alternative response to this problem is all the more significant.

Although approved plant-based human therapeutics now exist (e.g.: Gaucher's disease - lipid metabolism disorder), this is the first time a plant-based vaccine has been tested in a clinical trial. With further large-scale investigation, the promising field of plant-based vaccines can continue to grow, potentially providing alternative sets of solutions to medical problems.

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Danilo Glisic

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