It has been more than a year since the new crown pandemic. With the global acceleration of vaccination, the mutation of the virus strain in the pandemic has also become the focus of scientists' tracking. This poses a certain threat to the current anti epidemic achievements and the development of global epidemic situation.

Recently, Immunity published a study by Chinese team entitled "New Coronavirus mutant neutralizing antibody escape mechanism and expanding the use of other species ACE2 receptor" (Analysis of SARS-CoV-2 variant mutations reveals neutralization escape mechanisms mechanisms, China). This study confirmed the impact of multiple mutation sites of spike glycoprotein of mutant virus strain on neutralizing antibody escape and ACE2 use in different species, indicating that the mutant strain poses a severe challenge to antibody therapy and vaccine protection.

The findings of this study reveal the effects of COVID-19 mutant on current antibody drugs and neutralization ability in serum, providing key information and guidance for optimizing antibody drugs and designing the next generation of vaccines.

The corresponding authors of this paper are Professor Zhang Linqi, School of medicine, Tsinghua University, Professor Wang Xinquan, School of life sciences and Beijing advanced innovation center of structural biology, and Professor Zhang Tong, Beijing You'an Hospital, Capital Medical University. This is another important work of the team after a series of achievements in the research of anti neocrown antibody, which provides important scientific basis and guidance for the optimization of antibody drugs and vaccines.

The team mentioned that since the outbreak of New Coronavirus, the research team in the world has isolated high intensity neutralizing antibodies from infected blood samples and designed vaccines based on the sequence of the original virus strains. Now, a number of antibody drugs and preventive vaccines have been approved by the national and WHO regulatory authorities for emergency use (EUA).

These include the antibody cocktail therapy of Zaiyuan and Eli Lilly; Pfizer / biontech and Moderna company's mRNA vaccine; The adenovirus vector vaccines of Johnson & Johnson and AstraZeneca, as well as inactivated, adenovirus vector and recombinant protein vaccines in China.

It is noteworthy that, with the continuous popularity of COVID-19 in the world, the mutation of the virus is constantly accumulating, leading to the change of the antigenicity of the epidemic strains. At the end of last year, the British mutant b.1.1.7, the South African mutant b.1.351 and the Brazilian mutant P.1 began to spread on a large scale. The team pointed out that mutations in the spike proteins of these mutants are likely to affect the protective effects of current antibody therapy drugs and vaccines, as well as cross species transmission to other host animals.

In this study, the team constructed 28 new kinds of fake viruses, including three new crown mutation, single point mutation or multiple mutation, and evaluated the neutralizing ability of 12 neutralizing antibodies containing 7 clinical research antibodies and 23 sera from COVID-19 original strain (extracted from plasma of new crown cancer in 2020 1-2). Among the 12 kinds of antibodies, 11 are spike protein receptor domain (RBD) antibodies and one is spike protein N-terminal domain (NTD) antibodies. According to the recognition pattern and result characteristics, RBD antibodies are further divided into four categories (I, II, III and IV).

Among the three mutants, the South African mutant b.1.351 had the most obvious effect on the escape of monoclonal antibodies and convalescent plasma, followed by the Brazilian mutant P.1 and the British mutant b.1.1.7. The results showed that this resistance level corresponded to y144del and 242-244del mutations in NTD and k417n / T, e484k and n501y mutations in RBD. Mutations in NTD and RBD genes lead to changes in the major antigens of S protein.

So far, the most effective monoclonal antibodies isolated from infected and vaccinated individuals often target RBD, while many NTD monoclonal antibodies have not achieved 100% neutralizing activity. These results indicate that RBD antibody has a greater effect on plasma neutralization.

However, the study emphasizes that the emerging sars-cov-2 variant has more and more mutations in both NTD and RBD, which will challenge the effectiveness of monoclonal antibody therapy and vaccine protection.

In the case of monoclonal antibodies, the effect of these mutations is obvious. B. 1.351 and P.1 neutralization of many anti RBD and anti NTD antibodies, including two (CB6 and regn10933) that have been approved for use by the EUA.

The results show that k417n / T mutation can make most class I antibodies ineffective, e484k mutation can make class II antibodies ineffective, and triple mutant of "k417n-e484k-n501y" can make class I and class II antibodies ineffective. These three mutations are all located on the RBD of COVID-19 S protein. When the virus has three mutations at the same time, the immune escape ability will be greatly improved.

It is worth noting that the team also observed that a single k417n / T mutation tended to increase rather than decrease the neutralization activity of non class I McAbs. Since k417n / t also significantly reduces the binding to ACE2, this mutation may change the balance and facilitate the binding to antibody rather than ACE2. Similar results were found in convalescent plasma.

More importantly, the p2c-1f11 antibody in clinical research is hardly affected by single k417n / T mutation or triple mutation of "k417n-e484k-n501y". Previously, Zhang Linqi and others isolated 206 RBD monoclonal antibodies from the cells of patients with new crown infection, and screened p2c-1f11, p2b-2f6, p2c-1a3 and other high activity neutralizing antibodies. The test results were published in nature.

The study also pointed out that considering that most class I antibodies using heavy chain ighv3-53 / 3-66 lost efficacy for k417n mutation, p2c-1f11 results showed that there were class I antibodies not affected by the mutation. This provides hope for the induction of p2c-1f11 like antibody by vaccine, which can maintain strong and extensive neutralization activity against a variety of variants including b.1.351 and P.1.

It is worth mentioning that at the Pujiang innovation forum held recently, Chen Wei, a researcher of the Academy of Military Sciences, vice chairman of the Chinese Association for science and technology, and academician of the Chinese Academy of engineering, also mentioned the problem of virus mutation that is currently concerned by the outside world. She believes that the South African strain has a greater impact on the vaccine, and the vaccine for this mutation is also in clinical application, We hope to further cover the variation in the future.

In addition, this latest study found that COVID-19's ability to invade host cells by using mouse or mink ACE2 can be enhanced by mutations such as K417N/T, Y453F, E484K, F486L and N501Y.

They pointed out that this study is not necessarily equivalent to the natural infection and transmission of corresponding animals. However, the same k417n and / or n501y mutations found in sars-cov-2-adapted mice should attract enough attention, and these new mutations may be transmitted to mice and other animals.

In fact, the previously discovered sars-cov-2 variant in Danish mink farms has provided a warning signal that the host range of sars-cov-2 variant and the complexity of cross species transmission. The study points out that strict and thorough monitoring of relevant animals is needed to better understand this complexity and prevent future outbreaks.

In the discussion section, the research team pointed out that although the specific level of neutralizing antibody needed to provide protection is still uncertain, the reduction of antibody titer has aroused concern about its protection potential for emerging variants, especially b.1.351. In fact, studies have shown that the decrease of antibody titer in patients is related to the increased possibility of reinfection.

The team concluded that these results indicate that antigen transfer is taking place in the emerging sars-cov-2 variant. This requires immediate reassessment and update of monoclonal antibody therapies and vaccines. In the long run, the goal is to develop generic therapeutic and preventive interventions to maintain effectiveness for all mutant strains.