Although vaccination is no longer so effective in preventing COVID-19 infection, it is still one of the most cost-effective measures to prevent the epidemic.
Wen 丨 He Qianming
Edited by Gong Fangyi
In the last week of January 2020, a researcher got a black-and-white photograph that looked like a negative for starry sky photography, with black stars scattered across the white sky. But they are not actually stars, but spike proteins that are bred into specific shapes. This time, the researchers saw that the protein formed the shape that had the best chance of becoming a vaccine.
Five months later, the world's first COVID-19 vaccine was urgently put into use, and about 20 more vaccines have since been used to protect against the impact of COVID-19.
As vaccination rates gradually increase, the number of daily increased cases worldwide has steadily declined after WHO reported a record 810,400 new cases in a single day on 9 January 2021. After carrying the Delta variant strain, the daily increase in cases remained in the range of 300,000 to 500,000.
However, the Omicron variant discovered in South Africa last November reversed this trend, easily breaking through the immune barrier of 7.5 billion doses of vaccines and becoming the most dominant variant of the new crown virus in many countries or regions. In South Korea, Israel, the United States, the United Kingdom, Germany and other places, almost all of the new confirmed cases of the new coronavirus are infected with the Aumechjong variant.
Chart: The number of new confirmed cases of COVID-19 has skyrocketed daily since the emergence of the new coronavirus Omiljun strain in November 2021. From Wind.
At the same time, the new crown special drug developed at the same time as the vaccine and targeted at the original strain still shows a strong therapeutic effect on the Aomi kerong strain, and is regarded as an important supplement after the virus penetrates the protective power of the vaccine, helping to alleviate or avoid potential medical resource runs.
According to preliminary clinical trial data, the drug Molnupiravir developed by Merck and Ridgeback Biotherapeutics, as well as the oral specific drug of Paxlovid developed by Pfizer, can reduce hospitalization (severe) and mortality by 30% and 89% if taken within five days of COVID-19 infection.
In February 2022, Paxlovid became the first imported anti-epidemic drug approved by the State Food and Drug Administration of China since the outbreak of the new crown pneumonia epidemic. On March 9, China National Pharmaceutical Group signed an agreement with Pfizer pharmaceuticals to obtain the right to represent Paxlovid in Chinese mainland this year.
Why is it that the same research results based on the original new crown virus or early variants, the protective power of vaccines is significantly weakened, while the therapeutic effect of specific drugs has little loss? This is the core question we are trying to answer in this issue of TECH TUESDAY.
Vaccines and specific drugs operate in very different ways
The new coronavirus binds to the ACE2 receptor on the outside of human cells with the help of spike proteins, and then enters human cells, releasing the genome, hijacking protein translation and nucleic acid replication machines inside the cells, producing more viruses, infecting more human cells, and thus triggering symptoms.
People can find targets in the process of the virus binding to human cells or replicating in the human body to block the virus from infecting the human body.
Figure: The process by which the new coronavirus enters the human cell for replication, and the nodes that can be blocked. A paper published by a team from the Chinese Academy of Sciences.
Vaccines that play a preventive role target the spike protein on the new crown virus.
After humans are infected with the new crown virus and clear it with the help of the immune system, they will form immune memory with the spike protein on the virus as the "primer". Later, if human cells find a virus with the same spike protein, they will summon immune cells to clear it.
In other words, the spike protein is the equivalent of the "face" of the new crown virus, which is the key to the body's immune system recognizing the virus and clearing it.
Many vaccines are inactivated or inactivated (removed) of the new crown virus injected into the human body, so that the body's immune system recognizes the spike protein on the new crown virus, clears the virus and forms an immune memory.
There are also new vaccines that help the body form immune memory in other ways, such as the mRNA vaccine developed by Pfizer and BioNTech, which can guide human cells to produce nascent proteins on the new coronavirus that are harmless but enough to trigger an immune response.
Once the viral gene mutation – the spike protein has more changes – beyond the scope of the vaccine and the body's immune system, it will break through the protection. Clinical data show that no vaccine can prevent infection 100%.
The development of a special drug against the new crown virus is to find key proteins as "targets" in the process of virus replication to block viral replication. Different specific drug targets are different, which directly affects the effect and side effects of drugs.
For example, Paxlovid, a special drug developed by Pfizer, targets a protease called "3 CL", which is a key substance in the replication process of the new crown virus. The components in Paxlovid inhibit 3 CL protease, preventing it from functioning, and act as a barrier to viral replication.
3 CL protease is only present in the new coronavirus, not in humans. For safety reasons, Pfizer also has restrictions on people who take this drug: 12 years old and weighing more than 80 pounds.
Merck's Molnupiravir, on the other hand, adds the wrong ingredient to cause the virus to die when the virus replication is about to end and a new viral RNA is formed.
Because human cells themselves also have a process of synthesizing RNA, Merck's drugs are also considered to be potentially harmful to the human body, and experts recommend that pregnant women do not take them.
Spike proteins are more susceptible to mutation than drug targets
It is the root cause of the differentiation of vaccine and drug efficacy
As mentioned earlier, if the spike protein of the coronavirus is unchanged, the antibodies formed by people through vaccination or viral infection basically have strong protection. This is the reason why vaccines can prevent early strain infection, and it is also the root cause of the difficulty in defending against the infection of the Olmikron strain.
According to a paper published in the journal Nature by a research team at the University of Minnesota, more than 30 genetic mutations in the spike protein of Omi kerong compared to the original strain of the new coronavirus, most of which are concentrated in the places where it binds to human cells. The original Delta strain of the new coronavirus has only 3 mutations here.
This means that the immune memory formed by vaccinating a previously developed COVID-19 vaccine or infecting other strains of COVID-19 is difficult for cells to recognize and remove it in time.
Targets for oral specific drugs, such as Pfizer's Paxlovid-targeted 3CL protease, belong to the "conserved zone" of the coronavirus and basically do not have genetic mutations. According to the Stanford University Coronavirus Antiviral and Drug Resistance Database, the 3CL protease of the Omikeron strain has not changed compared to the original strain of the new coronavirus, so the Paxlovid effect will not be affected.
Now, new crown vaccine manufacturers such as Pfizer, Moderna, Kexing Bio, etc. have expressed their intention to develop vaccines against the Omiljung strain, but no new vaccine has been put into use.
Merck and Pfizer's special drugs have entered the mass production stage. Pfizer said at the end of 2021 that it will produce 120 million courses of Paxlovid in 2022, some of which will be sold at low prices to low- and middle-income countries, and the prices in countries with higher income levels are relatively higher. The U.S. government purchased 20 million courses of Paxlovid for $529 per treatment, or about 3,350 yuan.
Vaccination is no longer as effective at preventing COVID-19
However, it is still the most cost-effective means of epidemic prevention
In the past, it usually took more than 10 years for humans to discover a new virus and take a special drug for export, such as 15 years to develop a special drug against HIV, while the new crown virus special drug seems to have only taken two years.
This is the previous years of human research accumulation shortened the entire research and development time, in Pfizer's special drug Paxlovid, you can see people fighting SARS and AIDS.
Paxlovid has two components, one is Nirmatrelvir, which inhibits the 3CL protease. It can be traced back to Pfizer's development of anti-SARS virus drugs in 2002. Because the SARS epidemic passed quickly, drug research and development was shelved.
Another ingredient in Paxlovid is Ritonavir. It is a common drug used to treat AIDS and also inhibits proteases that play a role in viral replication. In the early days of the new crown epidemic, it was also used to treat patients infected with the virus, and after finding no effect, the World Health Organization recommended that it be discontinued. In Paxlovid, the role of ritonavir is to slow down the breakdown of nematvir in the human body, making it as long as possible to maintain its effect.
Merck's special drug, Molnupiravir, can be traced back to 2015 when scientists developed a treatment for the "Venezuelan equine encephalitis virus".
The same is true for vaccines. For example, the mRNA vaccine developed by Pfizer in collaboration with BioNTech is the result of a failure on AIDS in 2008.
Pharmaceutical companies and research institutes in many countries are now accelerating the study of specific drugs with guaranteed results, but the idea is mostly the same - to find targets that are not easy to mutate and are effective in the process of virus replication.
However, whether it is Merck or Pfizer's antiviral drugs, the main role is to treat mild to moderate patients infected with the new crown virus, reducing their probability of developing severe illness or death. For severe patients with new coronary pneumonia, there is currently no specific drug.
Although the vaccine is no longer so effective in preventing infection in the face of Aumechjong, it can help some people avoid symptoms of infection and have a high ability to prevent severe disease - the antibody memory formed by the original vaccine, even if it is impossible to recognize the spike protein on the Omiljung strain, the ability to clear the new crown virus is still there. According to China's National Health Commission, as of March 14, there were 11,984 confirmed cases of COVID-19 in Chinese mainland, compared with only 8 severe cases.
Many national health agencies and scientists also believe that the current effective way to combat the Olmikron strain, in addition to preventive measures such as isolation and wearing masks, is to inject the new crown vaccine to strengthen the needle. A large number of studies have also pointed out that no matter what kind of vaccine, after the injection of the third booster injection, it can effectively prevent the symptoms of people infected with the Omiljung strain for a period of time, and greatly reduce the probability of severe illness or death.
As Jura Biss, a doctor of immunology, writes in Immunology, the way vaccination works is by calling on most people to be vaccinated to protect a small group of people — who may be elderly, toddlers, or pregnant women — when enough immunocompetent people in the group are vaccinated to support the effects of herd immunity and help fight off disease.
"Public health is not just 'for' people like me, but 'through' we – really through our bodies – to make some of the measures that benefit the masses come to fruition." Yura Bees said.