A new coronavirus vaccine flew out of a moth? Scientists are working hard to make vaccines affordable for everyone

People are eager for the emergence of a new coronavirus vaccine to turn the tide, but there is a realistic question: Even if there is a vaccine, can everyone afford it? What factors should be considered in the pricing of vaccines?

As expected, the war between humans and the new coronavirus has entered a stalemate, but fortunately, good news favorable to the human camp has been coming one after another: Recently, two more inactivated new coronavirus vaccines produced by Chinese companies have been approved to enter clinical trials, and this is less than a month away from the clinical trials of the first vaccine with 108 volunteers.

It has to be said that the rapid development of high technology is indeed saving the future of mankind. However, compared to worrying about when a safe and effective COVID-19 vaccine will be available, the question we need to worry about more is - even if there is a vaccine, can everyone afford it?

(Photo source: CFP)

Can an affordable COVID-19 vaccine “fly” out of a moth?

If you want to discuss how much room there is for price reduction of a vaccine, you must first understand why it is priced so high.

When a virus invades the human body, some of its surface proteins are antigens that make people produce antibodies. Vaccination is to ensure that the virus does not cause disease, and to make the human body have such antibodies. To achieve this goal, scientists have developed many different types of vaccines using different technologies, such as live attenuated vaccines, inactivated vaccines, recombinant protein vaccines, viral vector vaccines, etc. Due to different manufacturing processes, these vaccines have different advantages and disadvantages, and their prices vary greatly.

At present, although emerging technologies such as genetic modification have brought huge opportunities to the vaccine industry, traditional vaccines represented by inactivated vaccines and live attenuated vaccines are still the main force in the vaccine market due to comprehensive factors such as process and cost. Generally speaking, the manufacture of such vaccines requires the use of eggs, bacteria, animals and insect cells as "incubators" to cultivate and isolate the viruses needed to make vaccines.

Against this backdrop, countries around the world are trying different technologies to develop COVID-19 vaccines in the hope of curbing the spread of the pandemic as soon as possible. In my country, researchers have adopted a "five-pronged" strategy, developing inactivated vaccines, nucleic acid vaccines, recombinant protein vaccines, adenovirus vector vaccines, and attenuated influenza virus vector vaccines at the same time, in the hope of finding a safe and effective vaccine as soon as possible. In the West, some scientists not only want to find an effective vaccine, they also want to keep the cost of the vaccine as low as possible, for example, using moth pests to develop COVID-19 vaccines.

It is understood that French pharmaceutical giant Sanofi recently announced that they plan to join forces with GlaxoSmithKline (GSK) to make full use of the FluBlok recombinant quadrivalent vaccine technology to develop a new crown vaccine. The highlight of this process is that the "raw materials" it uses are not common eggs, but the fall armyworms that are a headache for farmers.

As an invasive species, the fall armyworm has posed a serious threat to agriculture in many parts of my country in recent years. If this research and development is successful, it may provide scientists around the world with a more efficient and economical method to "turn waste into treasure" and produce new crown vaccines.

▲Fall armyworm larvae (Source: TheVaccineReaction)

Simply put, this technology requires extracting the required cells from the ovaries of the fall armyworm, and then using the gene-edited virus to infect these moth cells, so that these cells produce proteins on the surface of the virus. After extraction and purification, the researchers will mix these purified proteins with other necessary adjuvants to finally make a vaccine. After the vaccine is injected, these protective antigen proteins will stimulate the human immune system, allowing the human body to "rehearse" the invasion of the virus in advance, and prepare for the danger that may really come in the future.

Although it is still unknown whether the vaccine of Sanofi and GlaxoSmithKline will be successful, this technology provides more possibilities for "everyone to afford the new crown vaccine" - compared with traditional "chicken embryo" vaccines that use eggs as raw materials, this antiviral vaccine developed using insects has obvious advantages, especially in large-scale production.

On the one hand, this technology has a short production cycle, high efficiency, and greater throughput, making it easier to achieve the goal of large-scale production; on the other hand, the culture process of this protein has low risk and will not be subject to major changes due to the threat of avian influenza to chickens. Risk control is simple, and the cost of culture is relatively reasonable. In the case of high uncertainty in vaccine effectiveness and rapid virus mutation, this process using insects is more cost-effective. It is understood that in addition to the fall armyworm mentioned in the coronavirus vaccine, the cabbage looper has also been widely used as raw materials for antiviral vaccines.

Flu vaccines are so expensive, are eggs the culprit?

Can the "moth" really fly out a safe, effective and cheap new crown vaccine? Whether "turning waste into treasure" can succeed is still unknown, but one thing that can be confirmed is that if the new coronavirus will really plague humans for a long time as "flu 2.0", then the cheaper the vaccine, the more people's health can be protected. However, reality is often cruel - not to mention how high the requirements for research and development investment for new vaccines are, even reducing the price of the chicken embryo vaccine with the lowest research and development cost is quite difficult.

Take influenza vaccine as an example: At present, traditional influenza vaccine made from eggs is still the mainstream of the influenza vaccine market. The reason is that, on the one hand, in the process of cultivating influenza virus, the value-added efficiency of animal cell "cultivation of virus" is not ideal, the cost is extremely high, and the cost performance is too low; on the other hand, compared with using bacteria, animal and plant cells as virus incubators, eggs themselves contain a variety of proteins such as ovalbumin suitable for "cultivation of virus", which is very suitable for a variety of influenza viruses as a "breeding ground". In addition, as a traditional process with a long history, chicken embryo "seedling" is highly safe, easy to transport, and economical.

So, is the most affordable embryo-based influenza vaccine cheap enough for everyone to get one? It seems that it is still difficult. Why is even the embryo-based influenza vaccine so expensive? If we want to blame someone, we can only blame the eggs behind each vaccine, which are too "delicate".

First of all, ordinary eggs that can be bought in daily supermarkets cannot be used to "hatch viruses" because only fertilized eggs can be used as a culture medium for vaccines. At the same time, there are many complex requirements for raising hens that can produce these "hatching dishes", such as only feeding them pure natural feed and having sufficient living space... When these conditions are met, only chickens born between 30 and 56 weeks old will be kept to lay eggs. After the eggs are laid, they need to go through more than 10 days of incubation, and finally reach a state similar to "hairy eggs" before they can be truly put into use.

At present, many countries will classify the safety level of all aspects related to raising vaccine eggs as "involving national security". Not only is the location of the chicken farm a state secret and will a large number of security personnel be deployed to guard it, but the process of transferring the eggs from the chicken farm to the biosafety level 3 laboratory will also be equipped with bodyguards to oversee the entire transportation process.

▲Workers at a vaccine egg farm in Pennsylvania, USA, are sorting eggs for use (Source: CNN)

If these stringent conditions are met, can these "superior" eggs be used to develop vaccines? Of course not.

First, the eggs that pass the initial screening need to go through another manual screening process. The R&D staff will use an egg candling device to check each egg. Only eggs with clear and plump blood vessels in the eggshell will be kept, and the remaining "hairy eggs" will be discarded. After completing all the above steps, these eggs that have been disinfected can be truly regarded as sterile bioreactors and used as "incubators" for virus strains.

▲Technicians inject influenza virus strains into eggs (Source: CNN)

Subsequently, these selected "chicken embryos" will be placed on a conveyor belt and sent to complete the virus injection. Specifically, the virus will be injected into the allantoic cavity of the chicken embryo after being diluted, which is similar to the amniotic fluid of a human baby. In such a closed, sterile, constant temperature environment with rich sensitive cells, the virus will reproduce rapidly and eventually multiply into a large number of viruses. It takes at least 50-60 hours to complete the above process. During this period, this "virus egg" has extremely high requirements for many external factors such as temperature and light.

Finally, when a "virus egg" is truly "mature", the researchers will open the top cover of these eggs and use a needle to introduce the light red chicken embryo liquid in the amniotic cavity into a sterile tank. At this point, the egg's mission as a biological incubator is complete. After this, these liquids still need to be purified, inactivated and a series of complicated advanced processes before they can truly become the vaccines we are familiar with.

▲Schematic diagram of virus culture in the allantoic cavity of chicken embryos (Illustration: Beijing Science and Technology News/Wang Xueying)

Since the 1930s, humans have tried to use eggs to develop vaccines. Although the continuous upgrading of technology has reduced the cost, the various risks in each link still exist, which makes the cost of "chicken embryo" vaccine always high. Although the rise of genetic modification technology has provided more possibilities for vaccine manufacturing, many influenza vaccines around the world have still used this "chicken embryo" process in the past 80 years.

According to data from the U.S. Centers for Disease Control and Prevention, as of February 2020, 82% of the 174 million doses of influenza vaccines circulating in the U.S. market were made from "chicken embryos," and the U.S. government has invested billions of dollars just to raise these 140 million qualified "high-quality eggs." A document disclosed in 2017 showed that in order to obtain high-quality vaccine eggs, the U.S. Department of Health and Human Services signed a three-year cooperation agreement with a chicken farming company, investing $42 million just to obtain a one-year stable egg source provided by the company.

How difficult is it to reduce the price of vaccines through so many steps?

In fact, there are many factors that affect the pricing of a dose of vaccine, from R&D investment to mass production to market sales.

During the product development phase, the main cost of vaccines is the investment in R&D laboratories and professionals, which costs at least $500 million. If patent fees can be simplified or mature existing technologies can be used to develop new varieties, the cost of this link can be reduced to $135 million to $350 million.

▲Seqirus' vaccine R&D and production equipment (Source: Seqirus official website)

In terms of plant and equipment, the cost of vaccines mainly includes land acquisition, plant construction, equipment purchase and related maintenance. The cost of this stage can be as high as US$700 million and as low as US$50 million, depending on the complexity of the site, the degree of automation and other requirements. For example, Pfizer, the world's largest biopharmaceutical company, once invested US$600 million in five years to develop and produce Prevnar 13, a children's pneumococcal vaccine, and finally built a qualified new R&D and production workshop. Vaccines that can be produced on the same line will greatly reduce the company's investment in this aspect. Using disposable non-recyclable systems or reducing the degree of automation of equipment can also reduce the cost of this link.

In terms of manpower, labor cost expenditures for manufacturing usually do not exceed 1/4 of the total production costs, but companies still need to spend a lot of money in areas such as IT support and expert evaluation fees: the evaluation fee for traditional vaccines ranges from US$25,000 to US$100,000, and the annual fee can be as high as US$140,000.

Apart from these fixed investments, the approval process for a vaccine from leaving the laboratory to actually being marketed still requires a lot of manpower, energy and material resources. It took Pfizer's first Prevnar vaccine 14 years to be marketed.

▲The research and development of the new crown vaccine requires a lot of manpower, material resources and financial resources (Figure Note: Fort-russ)

Even an ordinary vaccine requires such huge financial support, and the situation of the COVID-19 vaccine that is urgently needed worldwide is even more grim. In order to alleviate the worries of enterprises, the Canadian government announced in early March that it would invest $275 million to help Canadian institutions develop vaccines. Similarly, the US Biomedical Advanced Research and Development Authority also stated that it would invest $1 billion to jointly develop vaccines with other companies.

However, can these national funds ensure that everyone can afford the new crown vaccine? After all, government support can only solve the initial funding difficulties. Whether it can encourage companies to independently develop and produce is the key to determining the fate of the vaccine.

Taking the Ebola virus vaccine as an example, the rVSV-ZEBOV vaccine, which entered research and development in early 2000, was not approved until 2019. Although clinical trials have proven its effectiveness during this period, the market demand is mostly in poor countries with limited economic strength, and the pricing of the vaccine cannot meet the development of the company, which ultimately led to the long-term shelving of the Ebola rVSV-ZEBOV vaccine.

Can the COVID-19 vaccine, which is in great demand, solve the contradiction between "enterprise autonomy" and "reasonable pricing" so that companies are willing to produce and manufacture while ensuring that everyone can afford it? In this regard, Alex Azar, secretary of the U.S. Department of Health and Human Services, believes that the situation is not optimistic. He admitted that despite the support of national finances, the price of the COVID-19 vaccine may not reach the "affordable" level. In the United States, it is unrealistic to want to make the vaccine affordable for the poor.

In contrast, in my country, as the first vaccine manufacturers approved to enter clinical research, Sinopharm Wuhan Institute of Biological Products, Beijing Sinovac Biotech and other companies have chosen Vero cell inactivated vaccines during their research and development. This process uses neither chicken embryos nor insect cells, but animal cells - macaque kidney cells. On the one hand, the advantages of Vero cell vaccine manufacturing are indeed obvious, such as effectively reducing pollution in the production process, fewer side effects, and higher safety, but on the other hand, there is also a disadvantage that cannot be ignored - high manufacturing costs.

It is expensive but necessary. How can humans coordinate the development cost and market pricing of the new crown vaccine? This may be a more difficult question to answer than developing a vaccine, and China’s answer to this is that "scientific research units do not count economic benefits, but only people’s health."

References

1. Stanley Plotkin, a James M. Robinson, The complexity and cost of vaccine manufacturing – An overview

2.https://www.statnews.com/2020/04/14/glaxosmithkline-sanofi-coronavirus-vaccine-collaboration/

3.https://thevaccinereaction.org/2017/10/armyworms-used-to-make-flublok-influenza-vaccine/#_edn4

4. https://www.cms.gov/Medicare/Medicare-Fee-for-Service-Part-B-Drugs/McrPartBDrugAvgSalesPrice/VaccinesPricing

5. https://www.nytimes.com/2014/07/03/health/Vaccine-Costs-Soaring-Paying-Till-It-Hurts.html

6.https://edition.cnn.com/2020/03/27/health/chicken-egg-flu-vaccine-intl-hnk-scli/index.html

Written by reporter Wang Xueying Edited by Liu Zhao

New Media Editor/Chen Xuanzhi

Produced by: Science Central Kitchen

Produced by: Beijing Science and Technology News | Science Plus Client

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