WANG Cai?hong, YAO Xiao?wen, WANG Rong, ZHOU Yu?xia, Li Bin, YU Xiao?hui, ZHANG Jiu?cong?

1. The First Clinical Medical College of Gansu University of Traditional Chinese Medicine, Lanzhou 730000, China

2. Department of Gastroenterology, the 940 Hospital of Joint Logistic Support Force of PLA, Lanzhou 730050, China

Keywords:SARS?CoV?2 Omicron variants BA.5 sub?variant Progess

ABSTRACT Since the outbreak of COVID?19, severe acute respiratory syndrome coronavirus 2 genome is still mutating, forming a variety of variants with strong transmission capacity, causing the spread of the epidemic worldwide, posing a serious threat to people's physical and mental health, and posing a major challenge to global public health. Omicron remains the main variant in several outbreaks worldwide, accounting for about 99% of the global genetic sequence.Recently, the World Health Organization announced that the subvariant of Omicron BA.5 has been found in more than 100 countries and regions around the world, causing the global epidemic rebound. However, there are few studies on the subvariant BA.5. This article reviews the latest research progress in epidemiology, infectivity, pathogenicity, vaccine and monoclonal antibody protection against Omicron subvariant BA.5, in order to provide reference for scientific prevention and control of Omicron subvariant BA.5.

1. Introduction

Coronavirus disease 2019 (COVID?19) caused by novel severe acute respiratory syndrome coronavirus 2 (SARS?CoV?2), COVID?19 has become a worldwide pandemic, bringing great harm and challenges to many countries and regions around the world. As of 29 July 2022, more than 571 million COVID?19 cases and 6.38 million deaths have been reported globally[1,2]. Omicron is still the main variant of many outbreaks in the world, accounting for about 99%of the global gene sequence[3]. This variant was first reported in South Africa on November 24, 2021, mainly includes BA.1, BA.2,BA.3, BA.4 and BA.5 subtypes. Among them, BA.1, BA.2 and BA.3 were the early circulating Omicron subtypes. This outbreak was caused by the new variant subtypes BA.4 and BA.5, which was mainly the more transmissibility BA.5, which made the global epidemic rebound[4].In this review, the epidemiology, infectivity,pathogenicity, protection of Omicron subvariant BA.5 by vaccines and monoclonal antibodies are reviewed.

2. Characteristics of the Omicron subvariant BA.5

2.1 Epidemiology

On July 20, 2022, WHO announced that in the past five weeks,the number of COVID?19 cases reported globally has been on the rise[5], with significant increases in the Western Pacific region, the Americas and Southeast Asia. The main cause is triggered by the more infectious Omicron subvariant BA.5[6].

On March 15, the Global Virus Gene Sharing Database (GISAID)collected the subvariant BA.5 gene sequence reported by South Africa for the first time, accounting for more than 50% of the new COVID?19 sequenced cases in South Africa. It triggered the fifth outbreak in South Africa in April and May, and then spread to the rest of the world within two months. It has become the main epidemic strain in South Africa, Portugal, the United Kingdom,Israel, Denmark, the United States and other countries, and is gradually rising in many European countries such as France and the Netherlands[7]. At present, BA.5 has been reported in 100 countries and regions, and continues to drive the increase in the number of infections, hospitalizations and intensive care unit admissions,becoming the mainstream virus in the new global epidemic[8,9]. In the global SARS?CoV?2 gene sequencing reported from July 4 to 10, the proportion of BA.5 increased from 51.84% to 53.59%, while the proportion of other Omicron subvariants reported in the same period was BA.4 (10.57%) and BA.2 (2.61%)[5]. The Centers for Disease Control and Prevention (CDC) reported at a White House press briefing on July 12 that the average number of COVID?19 hospitalizations in seven days was about 5100, double the number in early May[10].

On April 27, a patient infected with Omicron subvariant BA.5 was imported from abroad. The patient originated from Uganda on April 25, passed through Amsterdam, the Netherlands and Seoul,South Korea, and arrived at Shanghai Pudong International Airport on April 27. The nucleic acid test result was positive on April 29 and he was diagnosed with mild COVID?19. Genetic sequencing of a nasopharyngeal swab sample on May 13 revealed Omicron subvariant BA.5[11]. On July 2, xi 'an 1 nucleic acids found in key crowd DNA screening positive infection, on July 5, xi held the epidemic prevention and control conference say the positive patients infected with strains are BA.5.2 branch, the vast majority of related to recycling or its related personnel, virus from overseas,but the source is unclear, Xi 'an became the first city on the Chinese mainland to report a local outbreak of BA.5[12]. On July 6, a local outbreak of BA.5 infection was also reported in Beijing. According to the genetic sequencing results of the specimens of the three infected patients by members of the national COVID?19 Expert Group and the laboratory of the Beijing Center for Disease Control and Prevention, the virus all belonged to the branch BA.5.2. Based on the results of epidemiological investigation and gene sequencing,it was preliminarily considered that this outbreak was a local cluster caused by imported cases[13]. Subsequently, local outbreaks caused by BA.5 were reported in Tianjin, Zhuhai, Dalian, Qingdao and other cities[14]. Serious threat to human physical and mental health. If this trend continues, it is expected that BA.5 will almost completely replace BA.2 and become more dominant soon.

2.2 Infectivity

Compared with the Wuhan reference strain or other SARS?CoV?2 variants, including the highly infectious Delta variant, the Omicron variant has more mutation sites and is more infectious than other variants, and has been the predominant circulating strain in several outbreaks worldwide. However, the recently emerged Omicron subvariant BA.5 has become the mainstream strain in South Africa,Portugal, the United Kingdom and other countries. Local outbreaks caused by imported BA.5 have also been reported in Xi 'an, Beijing,Tianjin, Zhuhai and other cities in China.

Previous studies have shown[15] that the infectivity of SARS?CoV?2 mainly depends on the Receptor binding domain (RBD) and host Angiotensin converting enzyme 2 (Angiotensin converting enzyme 2, ACE2) binding affinity between target cell receptors. Studies have shown[16] that BA.4 and BA.5 have the same mutation sites as BA.2,and on this basis, they also have new mutation sites. Compared with BA.2, the S protein of BA.2 has added unique mutation sites DEL69?70, F486V, L452R and R493Q, resulting in enhanced binding affinity between the virus and host cells. Making the strain more contagious and the post?infection incubation period shorter.

A polynomial logistic regression model for South Africa estimated a daily growth advantage of 0.08 (95%CI: 0.08?0.09) for BA.4 and 0.10 (95%CI: 0.09?0.11) for BA.5[15]. The basic infectious numbers(R0) of the original strain, Delta, BA.1, BA.2 and BA.5 were reported to be 3.3, 5.1, 9.5, 13.3 and 18.6, respectively. It surpasses the measles virus, the most transmissible virus in recorded human history (R0 18). Compared with its predecessor BA.2, BA.5 is about 10%?30% more infectious, making it one of the most transmissible strains known so far. On 12 May 2022, the European Centre for Disease Control and Prevention (ECDC) reclassified BA.4 and BA.5 from Variants of Interest (VOI) to Variants of Concern (VOC)[17].

2.3 Pathogenic

In terms of pathogenicity, there are different voices in the research community. Kimura et al[18] evaluated the virulence of BA.5 based on the study of hamsters, and found that the RNA level around the lungs of hamsters infected with BA.5 strain was 5.7 times higher than that of hamsters infected with BA.2 strain 3 days after infection.Five days after infection, the RNA level of BA.5 was 4.2 times higher than that of BA.2. Within a week, BA.5?infected hamsters were more likely to experience shortness of breath, decreased subcutaneous oxygen saturation, and increased intermittent values of enhanced breathing. Co?infected hamsters were also more likely to develop bronchoconstriction, airway obstruction, and conditions such as bronchitis, alveolar damage, and congestion or bleeding in the lungs. This indicates that BA.5 is more pathogenic than BA.2.But the real world mortality rate of BA.5 severity, published in a preprint by South African scientists, was the original strain (5.3%),the Beta strain (6.9%), the Delta strain (6.4%), the BA.1 strain and the BA.4/5 strain (1.9%). The results indicated that BA.4/5 strain was less pathogenic than other strains[19].

The study found[20] that BA.4 and BA.5 resulted in similar hospitalization rates and slightly lower mortality rates than earlier Omicron strains in South Africa, and both Omicron surges proved to be much milder in terms of hospitalizations and deaths than the country's ferocious Delta wave. In Portugal, where COVID?19 vaccine and booster vaccination rates are very high, rates of death and hospitalisation caused by BA.4 and BA.5 were similar to those of the first wave of Omicron variants[21]. According to the present results, the pathogenicity of the Omicron subvariant BA.5 did not change significantly compared with the earlier Omicron strain.

2.4 Vaccine effectiveness

Vaccination is the most effective measure against COVID?19.Mutations in DEL69?70, L452R, F486V, and R493Q in the S protein of BA.5 that have recently surged may have attenuated the protective efficacy of vaccines already approved for use.

Arora et al[22] used serum of unvaccinated patients to neutralize BA.2.12.1, BA.4 and BA.5, and found that the neutralization efficiency of BA.1 was 2.9 times higher than that of B.1, and the neutralization efficiency of BA.1 was 27.2 times higher than that of B.1. However, the neutralization efficiency of BA.4 and BA.5 was significantly lower than that of BA.2 and BA.2.12.1 (only 1.6 times higher than that of B.1). In addition, the study further evaluated the neutralization effect of antibodies induced by vaccination, and found that after three doses of Pfizer?BionTech (BNT162b2) vaccine,BA.1, BA.2, BA.2.12.1, BA.4, and BA.5 escaped the neutralization effect of antibodies. Among them, the effect of and was reduced by 4.3 times, 4.2 times and 6.1 times respectively, and that of BA.4 and BA.5 was reduced by 8.1 times, indicating that BA.4 and BA.5 had stronger ability to escape neutralizing antibodies. Another study showed that BA.2.12.1 was only 1.8 times more resistant to serum from vaccinated and enhanced individuals than BA.2, whereas BA.4/5 was significantly more resistant (4.2 times) and thus more likely to lead to vaccine breakthrough infection[23]. However,vaccination has a strong protective effect in severe and fatal cases of BA.5 infection[18].

Bowen et al[24] also showed that almost all Omicron subvariants could evade the immune protective effect of the vaccine to a certain extent after the initial vaccination with COVID?19 vaccine or plasma neutralizing antibodies, but BA.5 had a stronger immune escape effect compared with the original strain or other subvariants. In addition, the study showed that subjects receiving a homologous or heterologous vaccine booster had significantly increased plasma neutralization activity and increased breadth and potency of neutralizing antibodies, providing sufficient protection against severe disease caused by Omicron.

2.5 Effectiveness of monoclonal antibodies and antiviral drugs

The development of monoclonal antibodies is another major breakthrough in the fight against COVID?19 after vaccines.In terms of COVID?19 prevention means, they can play a complementary role to vaccines. Previous studies have shown[25] that the BA.2 subvariant is less sensitive to certain monoclonal and polyclonal antibodies than the original Wuhan strain and other SARS?CoV?2 variants.Compared with BA.2, BA.4 and BA.5 have additional mutations such as L452Q, L452R and F486V located in the RBD of S protein.S protein is the main target of monoclonal antibody therapy.Therefore, the effectiveness of these mutations against US Food and Drug Administration (FDA)?approved monoclonal antibodies is of concern.

BA.5 neutralizing activity of four FDA?approved monoclonal antibodies such as sotrovimab, Bebtelovimab, Regen?CoV(casirivimab/imdevimab), and Evusheld (Tixagevimab/cilgavimab)was evaluated Sotrovimab[26], Casirivimab and Tixagevimab almost completely lost neutralizing activity against the subvariant BA.5,while Regen?CoV and Evusheld mab could still maintain neutralizing activity against BA.5. The effectiveness of the antibody was further evaluated by 50% Focus reduction neutralization test (FRNT50).The higher the value of FRNT50, the lower the neutralization activity.Compared with the original Wuhan strain, the FRNT50of BA.5 treated with Regen?CoV was 317.8, and the FRNT50of BA.5 treated with Evusheld was 30.7 times higher, indicating that the neutralizing activity of RegEN?CoV and Evusheld against subvariant BA.5 was still maintained. However, the neutralization activity was weaker than that of the original Wuhan strain. Only bebtelovimab could effectively neutralize BA.5, and FRNT50was similar to the original Wuhan strain.

Remdesivir and molnupirvir, inhibitors of the SARS?CoV?2 RNA?dependent RNA polymerase, and nirmatrelvir, an inhibitor of the master protease, have been approved by the FDA for the treatment of COVID?19[27]. Therefore, the study tested the sensitivity of these antiviral agents by determining the in vitro 50% inhibitory concentration (IC50) of each compound against BA.2.12.1, BA.4, and BA.5[25]. A higher value of IC50means a lower sensitivity. Compared with the amino acid sequence of the reference strain D614G, all three isolates encoded the P314L mutation of their RNA?dependent RNA polymerase and the P3395H mutation of their master protease.The results showed that the sensitivity of BA.2.12.1, BA.4 and BA.5 to the three compounds was similar to that of the original strain.For BA.2.12.1 subtype, IC50remdesivir was reduced 0.3 times,monopivir was reduced 1.1 times, and nimattrivir was reduced 0.7 times. For BA.4 subtype, IC50remdesivir decreased 0.7 times,while monopivir and nimatracivir increased 1.2 times and 1.1 times,respectively. For the BA.5 subtype, the IC50of remdesivir, monopivir and nimattrivir were 1.2, 1.5 and 1.6 times, respectively. The above data indicated that the three antiviral drugs approved by FDA had therapeutic effects on the three isolates, but the sensitivity of BA.5 to the three antiviral drugs was reduced compared with BA.2.12.1 and BA.4 subtypes.

3. Prevention and control strategies for Omicron subvariant BA.5

The Omicron subvariant BA.5 has the characteristics of short incubation period, strong transmission ability, and stronger immune escape ability, making the epidemic surge worldwide. However,the virulence is weak. Most patients show no symptoms or mild disease in the early stage, and they are still infectious, which has caused more infection cases when found. Among them, the existence of asymptomatic infected persons has brought great challenges to the prevention and control of the epidemic. Therefore, we should scientifically respond to the epidemic prevention and control of Omicron subvariant BA.5.

3.1 Adhere to the general strategy of "preventing external input and internal rebound" and the general policy of"dynamic zero clearing"

In terms of "foreign import prevention", we should prevent the risks of imported goods, strengthen the quarantine control and nucleic acid testing of inbound personnel. At present, the global epidemic is still in the stage of pandemic, adhere to the social consensus of not going abroad or leaving the country unless necessary or urgent, and minimize the local epidemic caused by overseas import. Within the"bounce" prevention, strengthen the new crown mobility control of epidemic areas, fight infection, strengthen clinic patients detection,in patients with suspected new champions such as fever, cough for nucleic acid detection, if the nucleic acid testing positive, to inform the community in a timely manner, and do early detection, early reporting, early isolation and early treatment; "Dynamic zeroing"does not mean "zero infection". Dynamic zeroing does not require that there will be no COVID?19 infection in the whole country at any time, but it requires that every outbreak should be put out in a short time. It is not equal to "social zeroing", but to achieve "social zeroing", to achieve "dynamic zeroing".

3.2 Improving self-epidemic prevention awareness

The primary measure for epidemic prevention and control is to publicize the knowledge of COVID?19 epidemic prevention and control and improve self?epidemic prevention awareness.The transmission mode of Omicron subvariant BA.5 is still mainly through droplet transmission. Therefore, normal epidemic prevention and control measures such as wearing masks, maintaining social distancing, washing hands frequently and ventilation are recommended.

3.3 Accelerate vaccine vaccination and research and development

Vaccination is the lowest cost measure for epidemic prevention.Current studies have shown that, compared with the original strain or other VOC, the protective efficacy of the vaccine against Omicron subvariant BA.5 is decreased, but it has a better protective efficacy against severe and fatal cases. Moreover, the neutralization effect of the antibody after vaccination with the booster vaccine is significantly improved compared with that after vaccination with the primary vaccine. People without obvious contraindications are encouraged to be fully vaccinated. As SARS?CoV?2 is still mutating,it is very important to monitor and analyze the mutated strains in time and optimize the vaccine development strategy.

4. Summary and prospect

Although two years have passed since the outbreak of COVID?19, variants are still rampant around the world. The Omicron variant, in particular, quickly gained dominance through its strong dispersal. The recently emerged Omicron subvariant BA.5 has the characteristics of short incubation period, fast transmission speed,and stronger immune escape ability. It is partially resistant to monoclonal antibodies and vaccine?induced immunity, and is surging worldwide, becoming the mainstream virus in the COVID?19 pandemic. Adding to the already overburdened epidemic prevention and control.

Although the subvariant BA.5 weakens the immune protection efficacy of vaccine and monoclonal antibody, it has a good protective effect in preventing severe and fatal cases. Therefore, people without contraindications are encouraged to get vaccine and booster shot as soon as possible, and those with poor vaccine effect are encouraged to use monoclonal antibody prevention. In addition, BA.5 is still mainly transmitted by droplets, so even if you are vaccinated against COVID?19 and/or vaccinated with monoclonal antibodies,you should wear a mask, maintain social distancing, wash your hands frequently, and have plenty of ventilation. At the same time,researchers should strengthen scientific research, timely monitor and analyze variant strains, and optimize vaccine development strategies to deal with Omicron subvariant BA.5 and future unknown variants.We believe that through the joint efforts of people from all countries,mankind will eventually overcome the novel coronavirus.

Description of author contribution

WANG Cai?hong: Participate in the main writing and revision of the article.YAO Xiao?wen,WANG Rong,ZHOU Yu?xia:Participate in relevant literature review.YU Xiao?hui, Li Bin,ZHANG Jiu?cong:Participate in the topic selection and design of the article.

All authors declare no conflicts of interest.