mRNA vaccine & inactivated vaccine, what are the differences in safety, effectiveness and accessibility?

The inactivated COVID-19 vaccine from Sinopharm Group, which is currently being given free to all Chinese citizens, took just over a year from research and development to market launch. Many people are wondering: Is the inactivated COVID-19 vaccine really safe and effective? How should we evaluate the COVID-19 vaccines that have been approved for marketing or authorized for use?

my country's current Drug Administration Law states: "Drug administration should be centered on people's health, adhere to the principles of risk management, full-process control, and social co-governance, establish a scientific and strict supervision and management system, comprehensively improve drug quality, and ensure the safety, effectiveness, and accessibility of drugs."

At a press conference held by the State Council Information Office in June last year, Wang Zhigang, Minister of Science and Technology, also stressed that "the most important signs of successful vaccine development are safety, effectiveness and accessibility."

So, what is the safety, effectiveness and accessibility of drugs? What are the differences between the inactivated vaccines and mRNA vaccines that have been approved for marketing or authorized for use in terms of safety, effectiveness and accessibility?

What are the safety, effectiveness and accessibility of medicines?

The U.S. Food and Drug Administration's regulations and guidelines for biological products (including vaccines) included in the U.S. Code of Federal Regulations define safety and effectiveness:

Safety: refers to the relative possibility of avoiding direct or indirect harmful effects of drugs on the human body based on a comprehensive consideration of the subjects' medication status and drug characteristics at the time.

In a broad sense, drug safety mainly involves three aspects: first, drug quality issues (mainly fake and inferior drugs); second, drug adverse reactions; and third, irrational drug use. As far as vaccines are concerned, since they are special drugs used for healthy people, their safety should be the first priority.

Vaccine safety evaluation and monitoring runs through the entire life cycle of the vaccine. Preclinical safety research is the key first step. It is necessary to complete experiments such as acute toxicity, repeated toxicity, immunogenicity, and animal attack protection in accordance with relevant laws and regulations and technical requirements. These experiments must meet the requirements and reach the specified standards. The second step is clinical research. Vaccine clinical trials are divided into four phases: Phase I clinical trials focus on observing the safety of use, mainly through a small number of susceptible populations to determine the human body's tolerance to different doses of the vaccine to understand the initial safety; Phase II clinical trials expand the sample size and target population, with the aim of confirming the preliminary effectiveness and safety results of the vaccine in the population, and determining the immunization program and immunization dose; Phase III clinical safety is conducted in the epidemic area to observe the occurrence of adverse reactions of different levels; Phase IV clinical trials mainly examine the efficacy and adverse reactions of the vaccine under conditions of widespread use.

Effectiveness: refers to the specific ability or efficacy of a drug to produce the intended effect, which is obtained by using appropriate test methods or clinical control study data based on the intended method of administration of the drug.

The effectiveness of a vaccine (also known as protective efficacy) refers to the degree to which the incidence of a disease is reduced in a population after vaccination relative to a non-vaccinated population (the percentage of reduced incidence). The effectiveness evaluation of vaccines is divided into two stages: preclinical research and clinical trials. Preclinical studies are mainly based on pharmacodynamic tests such as vaccine immunogenicity and in vivo protection in animals. In clinical trials, phases one and two are mainly used to observe the initial effectiveness of the vaccine, while phase three is the key effectiveness evaluation. This stage of research should use randomized, blinded, controlled clinical trials to determine the effectiveness of the vaccine. Generally, the final results of phase three clinical trials are the scientific basis for whether the vaccine can be approved for marketing.

The World Health Organization (WHO) proposed a definition of access to medicines in its essential drugs and medicines policy project.

Accessibility: means that everyone can safely and effectively obtain appropriate, high-quality and culturally acceptable medicines at an affordable price, and can easily obtain relevant information on the rational use of the medicines.

The factors affecting drug accessibility mainly include four aspects: rational use of medicines, affordable prices, sustainable financing and a credible health delivery system.

Safety, effectiveness and accessibility are interrelated and interdependent. Safety and effectiveness are the basis of accessibility, and accessibility is the "destination" of safety and effectiveness. Only when drugs are safe and effective can they cure diseases and save lives. However, no matter how safe and effective drugs are, they can only achieve their purpose of protecting and promoting public health if they are available to the people.

What are the similarities and differences in the “three characteristics” of the new coronavirus vaccines approved globally?

As of the end of December 2020, seven COVID-19 vaccines developed by companies around the world have been approved for marketing or emergency use. These COVID-19 vaccines mainly use three technical routes: inactivated, mRNA and adenovirus vectors. Below we will take the world's main inactivated vaccines and mRNA vaccines as examples to compare their differences in safety, effectiveness and accessibility.

Security

The inactivated vaccine technology is mature and has a history of more than 100 years. After decades of market verification, it is highly safe. In the immunization program around the world, inactivated vaccines account for a large proportion and are widely used in the prevention of many diseases. Long-term research and clinical use have proved that inactivated vaccines are very safe.

mRNA vaccines are instrumentally synthesized mRNA fragments that do not contain any viral components, which reduces the occurrence of allergic reactions and the safety risks caused by them. Its R&D threshold is high and its technology is cutting-edge, but it also faces challenges and risks. That is, although mRNA vaccines do not inactivate many allergens in viral vaccines, severe allergic cases can still occur, and its allergic mechanism is still unclear. In addition, since it is used for the first time on healthy people, the subsequent long-term effects are unknown and there is a certain degree of uncertainty.

Effectiveness

At present, only my country has approved the marketing of the inactivated COVID-19 vaccine. On December 30, 2020, the National Medical Products Administration approved the conditional marketing of the inactivated vaccine after reviewing and confirming the results of the Phase III clinical trial of the Sinopharm COVID-19 vaccine, which showed a protection rate of 79.34% and a neutralizing antibody positive conversion rate of 99.52%. Although the protection rate of this vaccine is lower than that of the mRNA vaccine, it exceeds the World Health Organization's minimum standard of 50% and the desired standard of 70%, showing good protection.

In principle, mRNA vaccines can not only stimulate the body's humoral immunity, but also induce T cell immunity. The dual mechanism of action enables the mRNA vaccine to be more than 90% effective. The mRNA COVID-19 vaccine jointly developed by Pfizer and Germany's BioNTech, which has obtained emergency use authorization from the UK Medicines and Healthcare Products Regulatory Agency (MHRA), has an efficacy of 95%. The Moderna COVID-19 vaccine, which has obtained emergency use authorization from the FDA, has an efficacy of 94.1%, both of which are higher than the inactivated vaccine.

It should be noted that it is not comprehensive to evaluate the protection efficiency of vaccines using only the data released by the companies. Since the infection rates of the new coronavirus in different sites where different vaccines are undergoing Phase III clinical trials are different, the statistical methods and judgment criteria are different, which will directly affect the value of the protection rate.

Accessibility

The inactivated vaccine production process is relatively simple, but the virus culture is required to be carried out under P3 biosafety conditions, which has some impact on the increase in production capacity. The advantage is that its storage conditions are 2-8°C, dark storage and transportation, and it is stable for 24 months (expected to be up to 36 months). This cold chain storage and transportation condition meets the global cold chain system standards, conforms to the national conditions of most countries, and greatly reduces the requirements for storage and transportation. The low cost of the cold chain is conducive to large-scale vaccination among the population and improves the accessibility of vaccines.

The development cycle of mRNA vaccines is short and the production process is relatively simple. As long as the gene sequence of the virus is known, a new candidate mRNA vaccine can be designed within a few days and can be produced quickly and on a large scale. However, due to the poor stability of RNA and its easy degradation, it must be stored at low temperatures. For example, the Pfizer vaccine needs to be stored and transported at -70°C, and the Moderna vaccine needs to be stored and transported at -20°C, which brings great inconvenience to the promotion and use of the vaccine.

In summary, whether it is an inactivated virus vaccine or an mRNA vaccine, their safety and effectiveness have been strictly controlled and fully met the standards before they are put on the market. The widespread vaccination of the new crown vaccine around the world will surely play a very important role in curbing the continued spread of the new crown epidemic.

Author: Contributed by Yaohuluwa Medical Biotechnology Popular Science Group