Plant-based vaccines – Have you ever imagined eating a vaccine?

Why do we need vaccines?

Well, we really understood why this last year with the Covid pandemic. We have been locked so many months inside our houses, avoiding each other, trying to survive and protect each other. There were moments that we felt scared, angry, fed up, frustrated and that we really begged for a solution, a miracle. But is it really a good option to expect a miracle? How can we take action? How can we prevent similar situations? How could we get well prepared to be able to respond to such “rare” and emergency situations? Do plants hold the keys to these answers?

Since the ancient times, microbial diseases are one of the leading causes of deaths worldwide. If we check the history microbial diseases were and are some of the most common reasons that had devastating effects on the social and economic life of several countries. Before the discovery of vaccines, microbial infections were major causes of death both in humans and animals. After vaccines were developed and applied worldwide the number of deaths caused by infectious diseases has significantly reduced¹. Apart from that, the discovery of vaccines has helped to eliminate many dangerous viruses such as smallpox, and type 2 poliovirus worldwide.

According to the World Wide Organization (WHO), there are currently available vaccines to prevent more than 20 life-threatening diseases. It is worth mentioning that due to vaccines 2-3 million deaths are prevented yearly from diseases like diphtheria, tetanus, pertussis, influenza and measles. We are pretty lucky to live in an era that vaccines exist. Thanks to them, we can enjoy longer and healthier lives and we have reduced significantly our socioeconomic problems.

Vaccines’ history in brief

People have understood the importance of developing immunity against microbes since the ancient times. According to history, inoculation attempts were taking place more than 2000 years ago in China and India for the elimination of smallpox virus. However, the person that is credited for the discovery of the first vaccine is Edward Jenner³.

Smallpox was a contagious and deadly virus especially for children and Jenner was the first one to publish scientific proof for the effects of vaccination as well as to propose a method to apply it. In 1796, he tried to vaccinate for smallpox a healthy 8-year-old boy named James Phipps. He inoculated him with fluid collected from pustules obtained from a woman, suffering from cowpox a similar virus. Surprisingly, the boy did not show any symptoms of smallpox infection and later when Jenner infected him with smallpox he managed to heal faster.

Later, Louis Pasteur observed that the attenuated strains of a pathogen can produce immunity in the host against the same organism. He named these weakened strains as vaccine (Latin vacca, meaning cow)⁴. After many attempts of vaccination worldwide, smallpox was finally eradicated in 1979 after having killed 300-500 million people.

Interestingly by 1900 there were two human virus vaccines, against smallpox and rabies, and three bacterial vaccines against, typhoid, cholera and plague. In 1974 the WHO adopted the goal of universal vaccination by 1990 to protect children against six preventable infectious diseases: measles, poliomyelitis, diphtheria, whooping cough, tetanus, and tuberculosis. During the 20th century many other vaccines against fatal infections were developed and today there are more than 20 vaccine preventable diseases.

Unfortunately, despite decades of mass vaccination polio remains a threat in India, Nigeria, Somalia, Niger, Afghanistan, Bangladesh and Indonesia⁵. In 2006 global health experts concluded that the eradication of polio is only possible if the supply of drinking water and sanitation facilities are improved in slums⁶. For a more detailed history of vaccination take a look here.

What is a vaccine and how it works

Vaccine is not exactly a drug. A drug is usually intended to treat a disease and relieve you from its symptoms. However, a vaccine cannot treat you from a disease, but it can activate your immune system to produce memory cells and antibodies against a certain invader, usually a virus or bacterium.

A vaccine is a complex biological preparation, a mixture of several biological components of a specific disease causing agent that provides active immunity to the humans and animals. According to World Health Organization (WHO), a vaccine is any preparation intended to produce immunity to a disease by stimulating the production of antibodies (WHO 2018).

So, what does this biological mix may contain? In order for your immune system to be activated, it needs to be exposed to a “foreign” to your body molecule. This can be a protein from a virus or a bacterium, the whole microbe, or another molecule that your body identifies it as “enemy”. All the vaccines are designed in such a way so as not to harm your body and create disease. Their goal is only to activate your immune system and help it produce “memory” against a specific microbe. On average it takes 12-36 months to manufacture a vaccine and quality control takes about 70% of the manufacturing duration.

What is immunological specificity

Antibodies (Ab), also known as immunoglobulins (Ig) are part of our immune system. You can imagine them as the specialized soldiers of your body’s army. They are so specific like a lock and a key. Antibodies are Y shaped proteins that have the ability to recognize specifically foreign molecules of other organisms, like viruses and bacteria. They are also “smart”. Through evolution, they have developed the ability to distinguish between foreign molecules (nonself components, NS) and molecules of your own body (self-components, S). The nonself components (NS) are also called antigens or toxins. 

Although specificity is a complicated and widely discussed subject between immunologists, we can simply say that it is the ability of an antibody to bind to one but not to another chemically similar substance. Thus, getting vaccinated is like training your army to recognize a molecule that is causing you a disease and building an army ready to defend you if you are infected from this substance.

What is immunological memory

If you fall sick due to an infectious pathogen your immune system needs some time to get activated, react and defend your body. This is quite risky as depending on your health, your diet, your age and the severity of the symptoms you may be able to heal quickly or not. However, if you are vaccinated your immune system gets in contact with elements of the pathogen that create the disease. Then, it produces antibodies and other cells like memory cells for example, but without you falling sick. Thus, getting vaccinated equips your immune system with memory. This means that your immune system is prepared and ready to defend you against a certain pathogen. If you are vaccinated and you get infected with this pathogen, your immune system will react faster than if you were not vaccinated. It will counteract this pathogen faster and the symptoms that you will experience will normally be milder.

How is a vaccine made?

Since the production of the first vaccine, many different types of vaccines have been developed. These vaccines vary in their production methods, stability, and mode of action. However, all vaccines are designed to trigger the immune response in the body. Here are the different types of vaccines that are currently available:

Types of vaccines

Live Attenuated Vaccines

A live attenuated vaccine contains live wild microbes which can cause a disease but which have been weakened. This means that a virus or bacterium that can create a disease has been modified in the lab in order not to induce disease anymore and has been multiplied in a host that is not specific for its reproduction in the nature. Thus, the attenuated vaccines include the whole pathogen but without its pathogenic properties.

This type of vaccines can mimic the original pathogen and trigger the immune system to produce a similar response, but without causing disease. The live attenuated vaccines usually produce a strong immune response that often lasts lifelong. Some common examples of live attenuated vaccines are the ones for measles, chickenpox and rubella. The disadvantage of this type of vaccines is that they take many years to be developed and they may cause serious side effects to people with immune system deficiencies (like HIV, leukemia or because of the treatment of several drugs).

Inactivated Vaccines

An inactivated vaccine contains killed microbes that have been killed by chemical or heat treatment in the lab. Sometimes the inactivated vaccines may not contain the whole microbe, but just one or more particles of it (for example only a protein of a microbe). As the inactivated vaccines do not contain live microbes, these microbes cannot replicate in the body of the vaccinated person, thus they are safer for people with immune system deficiencies. However, an inactivated vaccine provides low immunity therefore is needed to be administered in multiple doses. Some examples of inactivated vaccines are the ones for polio, hepatitis A, and rabies.

Subunit Vaccines

There are three types of subunit vaccines:

• The protein vaccines
• The polysaccharide vaccines
• The conjugate vaccines

For the production of the protein vaccines, a gene coding the vaccine protein of interest is inserted into a vector and subsequently expressed in a host system. A well-known example of a recombinant protein vaccine is the hepatitis B vaccine. Another type of protein vaccines are the toxoid vaccines. These vaccines are designed using the toxins that microbes produce after infecting the host and are responsible for creating disease to the host. Of course, the vaccine contains inactivated toxins which are not dangerous for the host. Examples of such vaccines are the diphtheria and tetanus vaccines.

Some other subunit vaccines, designed to prevent only bacterial infections are designed using polysaccharides, or sugars from the outer layer of the bacterial cells. These vaccines are also known as polysaccharide vaccines. Unfortunately, polysaccharide vaccines do not induce strong and long-term immunity.

This is why scientists developed the conjugate vaccines. In this type of vaccine, the polysaccharide is attached, or “conjugated,” to a protein antigen and offers improved protection. A common example of these vaccines is the vaccine against Haemophilus influenzae type B (Hib).

These vaccines are safe and possess minimum side effects due to the use of only a part of the infectious microbe. Interestingly, while most subunit vaccines focus on a particular pathogen, scientists also are developing vaccines that could offer broad protection against various diseases. Some of the diseases they are focusing are malaria, Zika virus, and dengue fever.

Nucleic Acid Vaccines

What are plant based vaccines

1. the egg-based vaccines

2. the cell-based vaccines and

3. vaccines produced using investigational-manufacturing systems

But what are investigational-manufacturing systems? They are systems that utilize biological organisms such as plants, insect cells, or bacteria cultures to manufacture vaccines. Among these, plants have received particular attention due to the numerous advantages they may offer. Currently, many plants have been used for the production of the plant vaccines such as tobacco, potato, tomato, banana, cereals, alfalfa, etc.

How plant based vaccines are produced?

In order to achieve the production of a vaccine in plants, scientists need to use biotechnology. First they need to insert the gene that codes for the antigen (coming from the pathogen) into the plant cells. In order to achieve that, they can use direct or indirect methods. One direct method is bombarding the plant cells with gold nanoparticles that have these genes attached to them (biolistic method). The indirect methods include either the insertion of these genes in some bacteria called Agrobacteria and then their transfer into the plants or the use of chimeric viruses. In this latter method, the scientists are transforming a plant virus by adding to it some genes of a human virus for example (chimeric virus). Then they infect the plants and the chimeric virus is being multiplied in the plant. Once the genes that code for the antigens are in the plant cells, the plant can produce edible fruits or vegetables that will contain them.

How plant derived vaccines work

Once a plant derived vaccine is produced it has to be of course approved from the FDA. After its’ approval, there are several ways to reach to us and help us acquire immunity. The simplest way would be to consume it directly as a raw fruit, vegetable or another part of a plant. However, the antigens could also be isolated from the plant and used for the development of tablets, capsules, and other pharmaceutical products.

After consuming a plant derived vaccine, our immune system is going to get activated and we are going to acquire long term immunity for a specific pathogen.

Vaccine safety: Risks and flaws

According to the WHO, ‘so few deaths can plausibly be attributed to vaccines that it is hard to assess the risk statistically’, and ‘serious adverse events occur rarely (on the order of one per thousands to one per millions of doses)’ (WHO, 2018).

For example, people who drive regularly have a high probability to be involved in a car accident; in the same way, people are very likely at some point of their life to be exposed to some infectious disease. Wearing a seat belt significantly reduces the risk that the car accident results in serious injury or death; analogically, in the case of infectious diseases, vaccines significantly reduce the risk that exposure results in serious injury or even death.

For a more detailed description of the different types of vaccines and their safety you can read a nice report from the WHO.

Safety of plant based vaccines

Plant vaccines are a type of subunit vaccines and commonly called edible vaccines. Plant-derived vaccines are considered safer and less toxic comparing to the conventional vaccines. This is because their production in plants offers high safety in the sense that they are not hosts of human or animal pathogens. On the contrary, vaccines produced in mammalian-based systems where the risk of contamination with viruses and prions exists are not so safe. Moreover, many plant tissues and fruits are safe for human consumption and thus can be used as safe oral delivery method for vaccines. This means less processing and production steps in the lab which are currently required for conventional injectable vaccines.

Until today, there are not many marketed vaccines produced in plants yet. Most of them are in the first or second clinical evaluation, but as this method of production is cheaper it will probably become very common in the future. However, there is a study published in 2020, which is one of the largest evaluations of a plant-derived vaccine. Doctors checked the efficacy and the safety of a plant produced flu vaccine [recombinant quadrivalent virus-like particle (QVLP) influenza vaccine] in more than 22000 participants. According to the results this vaccine is safe, well tolerated and protects against respiratory illness and influenza-like illness.

Advantages of plant based vaccines

The emergence of pandemic influenza strains (H5N1 and H1N1) as well as of SARS-CoV-2 (Covid19) have illustrated that conventional egg-based produced vaccines cannot meet global demand.
Plant vaccines are a cool and cost effective alternative to the current vaccination methods. Here is why:

1. They are cheaper because they are produced in transgenic plants and they need less equipment and technology.

2. They are safer because they can be delivered orally and there is no need of using needles and trained staff. Moreover, as they are produced in plants and not in animal cells their contamination with pathogens dangerous for the humans is reduced.

3. They can be produced in large scale and thus faster as plants provide higher yield of antigenic proteins compared to mammalian cell cultures.

4. They can be easily delivered to more people as they are more stable at high temperatures.

Disadvantages of plant based vaccines

1. Plant vaccines are not convenient for infants. Their dose may vary based on age and size of plant product (fruit and tubers) since diversity in age and size of plant product may express different levels of protein.

2. Possibility of contamination of plant products or vaccines with mycotoxins, pesticides, and insecticides is capable of causing side effects in the humans.

3. The presence of certain toxic plant compounds could produce adverse reactions in humans.

4. In addition, mixing of transgenic plants with their normal counterparts can cause overdose of the vaccine in the consumers.

5. It is difficult to evaluate the required dosage for every patient. Two people with different body weight and age, require different dose of vaccine.

There are also some bioethical issues arising from the production of plant-based vaccines. One of them is the transferring of allergenic compounds from transgenic plants to humans and animals. Furthermore, as for the production of some plant-based vaccines bacteria and viruses are used, the pathogens might be reactivated and infect other organisms that consume them. Thus, it would make sense to grow such plant derived vaccines in controlled environments so as pollen, seeds or other parts of the plants are not spread in the environment. However, that would compromise the scale of the production and could restrict the amounts of vaccines that can be produced fast in case of an emergency.

The ultimate goal would be to produce stable plant based transgenic vaccines which are safe for consumption while reducing the production cost and not harming the environment.

Examples of plant based vaccines

(a) plant made monoclonal antibody (scFV mAB) used in the production of a recombinant Hepatitis B (HBV) vaccine in Cuba and

(b) Newcastle disease virus (NDV) vaccine for poultry approved by the US Department of Agriculture (USDA).

There is no plant based vaccine that has received the green light from the US Food and Drug Administration (FDA), yet. This is mostly due to the fact that plant based vaccines are classified under the genetically modified crop category.

By 2019, a total of 11 human clinical trials had been completed using plant-based virus like particles (VLP) vaccines, including two phase III trials for a Quadrivalent influenza VLP vaccine. The results of some of them showed that the development of plant derived vaccines are promising. There are many other clinical trials taking place currently for the production of plant derived vaccines. These vaccines include the development of vaccines for several flu strains, for Ebola, for Anthrax as well as for malaria.

Take home message

Plant-based vaccines are the emerging type of vaccines that can offer us a higher therapeutic value and help us treat many human and animal diseases faster. The benefits and advantages of plant based vaccines could take us to a new era. Hopefully, thanks to the hard work of scientists and their collaboration with companies and governments, the challenges faced by these interesting biological products can be tackled appropriately. It seems logical that their regulatory approval will be granted at some point so as we can manage the diseases globally. So, we should not be surprised if in a few years or decades if we start eating our vaccines in the form of fruits, vegetables or other plant parts.