Omicron is the most serious mutation so far. There are more than 30 mutations in spike protein, 15 of which occur in receptor binding domain (RBD). This COVID-19 mutant poses new challenges to scientific research and epidemic prevention decision-making. A recent study published in Nature, a top academic journal, pointed out that a key question for China is whether the inactivated vaccine that has been inoculated on a large scale also has a severe protective effect on Omicron mutant.
On January 28th, Nature published a study jointly completed by researchers from the Institute of Biophysics of Chinese Academy of Sciences, the Institute of Medical Experimental Animals of China Academy of Medical Sciences, the Institute of Microbiology and Epidemiology of the Academy of Military Medicine of the Academy of Military Sciences, China Institute of Food and Drug Control (NIFDC), Beijing Kexing Biological Products Co., Ltd., etc. The research team systematically analyzed the titer of neutralizing antibodies in the serum of volunteers vaccinated with CoronaVac and the antibody spectrum of memory B lymphocytes.
The research was led by researcher Wang Xiangxi from Institute of Biophysics of Chinese Academy of Sciences and Key Laboratory of Infection and Immunity of Chinese Academy of Sciences. Other correspondents included researcher Qin Chengfeng from Institute of Microbiology and Epidemiology of Academy of Military Medicine of Chinese Academy of Military Sciences, Wang Youchun, chief expert of vaccine testing of China Food and Drug Testing Institute, and Qin Chuan, director of Institute of Medical Experimental Animals of China Academy of Medical Sciences.
It is mentioned in the paper that although the currently approved COVID-19 vaccine continues to be effective against serious diseases and deaths caused by Delta mutants, the third dose of vaccine or even the development of new vaccine is needed due to the decreased immunity and large-scale breakthrough infection caused by virus mutation.
Previously, on December 8, 2021, Pfizer announced that a preliminary laboratory study showed that three doses of Pfizer /Biontech mRNA COVID-19 vaccine BNT162b2 could neutralize the mutant strain in Omicron, Covid-19. Compared with two doses of vaccine, inoculation of three doses of the vaccine increased the titer of neutralizing antibody by 25 times.
The research team believes that these preliminary data about Omicron neutralization sensitivity need further independent verification, and the clinical effects of natural immunity and vaccine-induced immunity in preventing infection and serious diseases also need urgent investigation. As far as China is concerned, inactivated vaccine has been inoculated on a large scale up to now. Does this also have a serious protective effect on Omicron mutant? What is the necessity of three doses of vaccination?
In this study, Wang Xiangxi et al. collected the sera of 60 volunteers who had been inoculated with inactivated vaccine twice (in the procedure of October and January) and 60 volunteers who had been inoculated with inactivated vaccine three times (in the procedure of October, January and July), and evaluated their neutralization titer against the original strain and Omicron mutant by COVID-19 live virus neutralization test. None of these volunteers were infected with Covid-19 before the study, and blood samples collected four weeks after the last vaccination were used in the study.
Evolution and neutralization characteristics of Omicron mutant.
The data showed that the geometric mean median maximum neutralization titer (GMT NT50) of the volunteers inoculated with three doses of inactivated COVID-19 vaccine against wild-type (WT) virus, Delta and Omicron mutant were 253.9, 77.8 and 15.4, respectively. Compared with the wild-type virus, the semi-maximum neutralization titer of Delta and Omicron decreased by 3.3 times and 16.5 times respectively. Three of the 60 volunteers had an NT50 titer of less than 8 for Omicron. In other words, the seroconversion rate of neutralizing antibody against Omicron in volunteers vaccinated with three doses of inactivated COVID-19 vaccine was 95%.
However, they mentioned in their research that what deserves more attention at present is the effectiveness of the two-dose vaccination program for Omicron infection. In the two-dose inoculation group, compared with the wild-type (WT) virus, the NT50 titer of Delta was 6.6, which was 5.1 times lower. Notably, none of the 60 volunteers had a serum sample with an NT50 titer greater than 8 for Omicron.
These results showed that the neutralizing ability of COVID-19 mutant strain was poor after inoculation with two doses of inactivated vaccine, and the neutralizing antibody titer in vivo could be improved by inoculation with the third dose of inactivated vaccine. However, the titer of neutralizing antibody against Omicron mutant was still low. The research team believes that their data is consistent with previous observations, that is, three doses of inactivated vaccine inoculation can enhance the neutralization breadth of SARS-CoV-2 mutant.
Strengthen the characteristics of broad-spectrum neutralizing antibodies in needle volunteers.
It is worth noting that after the existing vaccination, the level of neutralizing antibody in serum is not enough to fully curb breakthrough infection, so why can it effectively provide severe protection?
The research team isolated immunoglobulin (IgG+) memory B cells from peripheral blood mononuclear cells (PBMCs) of four three-dose vaccinators, obtained the sequences of antibody heavy chain and light chain variable regions and expressed 323 strains of antibodies in vitro. They found that 163 antibodies recognized virus RBD, 100 antibodies recognized NTD and 51 antibodies recognized S2. The test results also showed that almost all antibodies that bind to RBD can bind to wild-type strains, among which 127 antibodies have neutralizing activity against wild-type strains of real and pseudoviruses, and they chose these antibodies for further study.
Among these 127 strains of antibodies, more than 93% showed extensive binding activity to most of the mutants of concern and interest. It is worth noting that 85% of these antibodies cross-react with Omicron RBD.
In contrast, about 80% of NTD-binding antibodies lost their cross-reaction with Omicron. In addition, due to the great diversity of NTD, the cross-reaction of NTD antibody to the other four variants of concern is relatively poor.
Their research also found that among the antibodies binding to RBD region, 31 strains can effectively neutralize wild-type pseudoviruses and true viruses and all concerned variants, and the semi-inhibitory concentration IC50 is between 0.002 and 0.800μg/ml. Among them, 30 strains of antibodies can directly block the binding between RBD and ACE2.
Among the 31 strains of broad-spectrum potent antibodies isolated in this study, 13 strains have IC50 less than 0.02ug/ml to Omicron, which is 10-40 times as high as that of VIR-7831 from GSK/Vir and DXP-604 which is still in the clinical trial stage in China.
The structural basis of extensive and effective neutralization of representative antibodies.
The research team also selected four antibodies for further structural biological analysis. Among them, XGV347 (class II antibody) and XGV289 (class IV antibody) have strong neutralizing activity against all concerned mutants, including Omicron.
They also identified the interaction between these antibodies and Omicron spike protein, and identified a mutation G446S of spike protein, which is more resistant to a class of antibodies that bind to the receptor binding domain and is a key escape site.
Structural comparison shows that XGv347 is similar to a neutralizing antibody (A23-58.1) which is effective against several Covid-19 mutants, and is similar to the epitope (antibody binding site) targeted by another neutralizing antibody (S2K146). It is worth noting that S2K146 is effective against other strains of coronavirus B (i.e., subgenus sarbecovirus, a group of virus strains to which Covid-19 belongs).
Further experiments in this study also show that the representative broad-spectrum neutralizing antibody therapy has a high protective effect on the infection of beta mutant and Omicron mutant in mice.
Protective effect of neutralizing antibody therapy on infection of beta mutant and Omicron mutant in mice.
The research team believes that this study proves that the three-dose vaccination program is reasonable under the current pandemic. At the same time, antibodies that identify and identify epitopes in the same region can be classified, and different types of antibodies can form cocktail therapy, which can be used to prevent and treat current epidemic strains and new strains that may appear in the future, or help to develop a general vaccine strategy for branch B of coronavirus B.
Original link: https://www.nature.com/articles/s41586-022-04466-x