Home » Extensive humoral immune evasion contributes to the emergence and rapid spread of the Arg346-mutated BA.4 and BA.5 sublines.

Extensive humoral immune evasion contributes to the emergence and rapid spread of the Arg346-mutated BA.4 and BA.5 sublines.

by archyde

In a recent study published in The Lancet Infectious Diseasesresearchers measured the neutralization titers of plasma samples against the Omicron novel variant of concern (VOC) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) subvariants BA.4 and BA.5 with mutations in arginine (Arg)346.

Study: Further humoral immunity evasion of emerging SARS-CoV-2 subvariants BA.4 and BA.5. Image credit: Alexyz3d/Shutterstock


The receptor-binding domain (RBD) region of the SARS-CoV-2 spike (S) glycoprotein in the Omicron BA.4 and BA.5 subvariants continually acquires mutations. Several countries have witnessed the increase in BA.4/BA.5 subvariants with Arg346 S mutations, namely BA.4.6, BA.5.2.6, BA.4.1.9, BF.7 and BE. 1.2. While these mutated Omicron subvariants have the Arg346Threonine (Thr) mutation, others, such as BA.4.7, BF.13, and BA.5.9, have the Arg346Serine (Ser) and Arg346Isoleucine (Ile) mutations, respectively.

Notably, some of these Omicron sub-variants, particularly BA.4.6, thus gained a growth advantage over others, including the predecessor strains BA.4 and BA.5. Numerous studies have shown that Arg346 is an important immunogenic amino acid residue that gives SARS-CoV-2 the ability to evade neutralizing antibodies. There is therefore an urgent need to evaluate drugs and vaccines against the Omicron BA.4 and BA.5 subvariants. In this context, it should also be noted that, unlike the mutation of Arg to Lysine (Lys) in BA.1.1, mutations of Arg to Thr, Ser or Ile resulted in a more severe change in antibody recognition. .

About the study

In the current study, researchers obtained plasma samples from people who received three doses of CoronaVac after breakthrough infection with Omicron BA.1, BA.2, or BA.5 or without SARS-CoV-2 infection. They took plasma samples three to five weeks after the infection broke through, confirmed by reverse-transcription polymerase chain reaction (RT-PCR).

Additionally, the team used pseudoviruses based on vesicular stomatitis virus (VSV) in the neutralization assays. Through these assays, the team determined the pseudovirus neutralizing activities of 11 monoclonal antibodies and four antibody cocktails against the Arg346-mutated sublines BA.4 and BA.5.

Study results

Individuals uninfected with SARS-CoV-2 who received a three-dose regimen of CoronaVac showed a 50% decrease in neutralization titers (NT50) in the range of 1.5 to 1.7. The decrease in the multiplication factor was more pronounced for the BA.5.9, BA.4.6 and BA.4.7 sublines than for BA.4 or BA.5, because the former had Arg346Ile, Arg346Thr and Arg346Ser mutations. BA.4/BA.5 sublines with these mutations could also escape plasma neutralization of BA.5 breakthrough cases. In addition, they exhibited a 2.4 to 2.6 fold decrease in NT50. Conversely, BA.1.1 also exhibited immune evasion potential as it carried an Arg346Lys mutation similar to that of BA.1.

The researchers noted nearly identical reductions in neutralization titers in convalescents recovering from BA.1/BA.2 infections. Additionally, they found that plasma from BA.5 convalescents showed higher neutralization titers against BA.5 than against BA.1.1 and BA.1. However, convalescent plasma from BA.1, BA.2 and BA.5 infection cases was more effective against the ancestral strain of SARS-CoV-2 carrying the Asp614Gly mutation. According to the authors, one or more phenomena of immune imprinting or original antigenic sin are probably at the origin of these observations.

Cilgavimab could not neutralize BA.4 and BA.5 sublines with Arg346Ile, Arg346Thr, or Arg346Ser mutations. Thus, the antibody cocktail Evusheld, a combination of tixagevimab and cilgavimab, remained ineffective against the BA.4.6, BA.4.7, BA.5.2.6 and BA.5.9 sublines. Similarly, the REGEN-COV cocktail, a combination of casirivimab and imdevimab, showed reduced reactivity against the Arg346 mutated sublines. In particular, bebtelovimab remained highly effective against sublines with these mutations.


The current study showed enhanced humoral immunity evasion ability of BA.4 and BA.5 sublines with Arg346 mutations. This observation has two important implications. First, the Omicron BA.4.6, BA.4.7, BA.5.9, BF.7, BA.5.2.6, BA.4.1.9, BE.1.2 and BF.13 sublines could benefit from a transmission advantage during the ongoing COVID-19 pandemic. Second, this immune evasion could lead to the emergence and rapid spread of multiple Arg346-mutated BA.4 and BA.5 sublines.

In addition, there is a possibility of potential BA.4.6 reinfections after recovery from BA.4 or BA.5 infection. In addition, people with immunodeficiencies or comorbidities are at greater risk of reinfection with Omicron subvariants. The authors insist above all on the evaluation of vaccines targeting the BA.4 and BA.5 sub-variants.

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