SARS-CoV-2、ο株、とりわけ BA.5 に関して

投稿日投稿者しとらす

こういったことを話させたら、日本のツイッタらんどでは最強と目されているラモスさんのツイートから、BA.5 関連を中心に拾いました。備忘録代わり。

③1つだけ。重症化予防に寄与している可能性のある機序がある。

それがIFNだ。
ウイルス感染する→抗ウイルス成分を生体が出して戦う→戦いが延長戦に入ってしまうと生体の対感染反応(発熱とか)が酷くなりすぎて入院→運が悪いとサイトカインストーム。

これが重症化https://t.co/umgkEGCIqb

— ramos2 (@ramos262740691) June 9, 2022

◆Neutralization Escape by SARS-CoV-2 Omicron Subvariants BA.2.12.1, BA.4, and BA.5【NEJM　2022年7月7日】

In recent months, multiple lineages of the omicron (B.1.1.529) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged,1 with subvariants BA.1 and BA.2 showing substantial escape from neutralizing antibodies.2-5 Subvariant BA.2.12.1 is now the dominant strain in the United States, and BA.4 and BA.5 are dominant in South Africa (Figure 1A). Subvariants BA.4 and BA.5 have identical sequences of the spike protein.

We evaluated neutralizing antibody titers against the reference WA1/2020 isolate of SARS-CoV-2 along with omicron subvariants BA.1, BA.2, BA.2.12.1, and BA.4 or BA.5 in 27 participants who had been vaccinated and boosted with messenger RNA vaccine BNT162b2 (Pfizer–BioNTech) and in 27 participants who had been infected with the BA.1 or BA.2 subvariant a median of 29 days earlier (range, 2 to 113) (Tables S1 and S2 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). In the vaccine cohort, participants were excluded if they had a history of SARS-CoV-2 infection or a positive result on nucleocapsid serologic analysis or if they had received another vaccine against coronavirus disease 2019 (Covid-19) or an immunosuppressive medication.

Six months after the initial two BNT162b2 immunizations, the median neutralizing antibody pseudovirus titer was 124 against WA1/2020 but less than 20 against all the tested omicron subvariants (Figure 1B). Two weeks after administration of the booster dose, the median neutralizing antibody titer increased substantially, to 5783 against the WA1/2020 isolate, 900 against the BA.1 subvariant, 829 against the BA.2 subvariant, 410 against the BA.2.12.1 subvariant, and 275 against the BA.4 or BA.5 subvariant. These data show that as compared with the response against the WA1/2020 isolate, the neutralizing antibody titer was lower by a factor of 6.4 against BA.1, by a factor of 7.0 against BA.2, by a factor of 14.1 against BA.2.12.1, and by a factor of 21.0 against BA.4 or BA.5. In addition, as compared with the median neutralizing antibody titer against the BA.1 subvariant, the median titer was lower by a factor of 2.2 against the BA.2.12.1 subvariant and by a factor of 3.3 against the BA.4 or BA.5 subvariant.

Among the participants who had been infected with the BA.1 or BA.2 subvariant of omicron, all but one had been vaccinated against Covid-19. Because of the variation in sampling after the onset of infection, some samples may not reflect peak neutralizing antibody titers (Table S2). Among the participants with a history of Covid-19, the median neutralizing antibody titer was 11,050 against the WA1/2020 isolate, 1740 against the BA.1 subvariant, 1910 against the BA.2 subvariant, 1150 against the BA.2.12.1 subvariant, and 590 against the BA.4 or BA.5 subvariant (Figure 1C). These data show that as compared with the WA1/2020 isolate, the median neutralizing antibody titer was lower by a factor of 6.4 against BA.1, by a factor of 5.8 against BA.2, by a factor of 9.6 against BA.2.12.1, and by a factor of 18.7 against BA.4 or BA.5. In addition, as compared with the median titers against the BA.1 subvariant, the median titer was lower by a factor of 1.5 against the BA.2.12.1 subvariant and by a factor of 2.9 against the BA.4 or BA.5 subvariant.

These data show that the BA.2.12.1, BA.4, and BA.5 subvariants substantially escape neutralizing antibodies induced by both vaccination and infection. Moreover, neutralizing antibody titers against the BA.4 or BA.5 subvariant and (to a lesser extent) against the BA.2.12.1 subvariant were lower than titers against the BA.1 and BA.2 subvariants, which suggests that the SARS-CoV-2 omicron variant has continued to evolve with increasing neutralization escape. These findings provide immunologic context for the current surges caused by the BA.2.12.1, BA.4, and BA.5 subvariants in populations with high frequencies of vaccination and BA.1 or BA.2 infection.

◆BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron infection【nature 2022年6月17日】

Abstract

SARS-CoV-2 Omicron sublineages BA.2.12.1, BA.4 and BA.5 exhibit higher transmissibility over BA.2. The new variants’ receptor binding and immune evasion capability require immediate investigation. Here, coupled with Spike structural comparisons, we show that BA.2.12.1 and BA.4/BA.5 exhibit comparable ACE2-binding affinities to BA.2. Importantly, BA.2.12.1 and BA.4/BA.5 display stronger neutralization evasion than BA.2 against the plasma from 3-dose vaccination and, most strikingly, from post-vaccination BA.1 infections. To delineate the underlying antibody evasion mechanism, we determined the escaping mutation profiles, epitope distribution and Omicron neutralization efficacy of 1640 RBD-directed neutralizing antibodies (NAbs), including 614 isolated from BA.1 convalescents. Interestingly, post-vaccination BA.1 infection mainly recalls wildtype-induced humoral memory. The resulting elicited antibodies could neutralize both wildtype and BA.1 and are enriched on non-ACE2-competing epitopes. However, most of these cross-reactive NAbs are heavily escaped by L452Q, L452R and F486V. BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1; nevertheless, these NAbs are largely escaped by BA.2/BA.4/BA.5 due to D405N and F486V, and react weakly to pre-Omicron variants, exhibiting poor neutralization breadths. As for therapeutic NAbs, Bebtelovimab and Cilgavimab can effectively neutralize BA.2.12.1 and BA.4/BA.5, while the S371F, D405N and R408S mutations would undermine most broad sarbecovirus NAbs. Together, our results indicate that Omicron may evolve mutations to evade the humoral immunity elicited by BA.1 infection, suggesting that BA.1-derived vaccine boosters may not achieve broad-spectrum protection against new Omicron variants.

◆SARS-CoV-2 Omicron BA.5: Evolving tropism and evasion of potent humoral responses and resistance to clinical immunotherapeutics relative to viral variants of concern【medRxiv　2022年7月10日】

Abstract

Genetically distinct viral variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been recorded since January 2020. Over this time global vaccine programs have been introduced, contributing to lower COVID-19 hospitalisation and mortality rates, particularly in developed countries. In late 2021, the Omicron BA.1 variant emerged, with substantially different genetic differences and clinical effects from other variants of concern (VOC). This variant demonstrated higher numbers of polymorphisms in the gene encoding the Spike (S) protein, and it has displaced the previously dominant Delta variant. Shortly after dominating global spread in early 2022, BA.1 was supplanted by the genetically distinct Omicron lineage BA.2. A sub-lineage of BA.2, designated BA.5 has now started to dominate globally, with the potential to supplant BA.2. To address the relative threat of BA.5, we determined infectivity to particle ratios in primary nasopharyngeal samples and expanded low passage isolates in a well characterised, genetically engineered ACE2/TMPRSS2 cell line. We then assessed the impact of BA.5 infection on humoral neutralisation in vitro, in vaccinated and convalescent cohorts, using concentrated human IgG pooled from thousands of plasma donors, and licensed monoclonal antibody therapies. The infectivity of virus in primary swabs and expanded isolates revealed that whilst BA.1 and BA.2 are attenuated through ACE2/TMPRSS2, BA.5 infectivity is equivalent to that of an early 2020 circulating clade and has greater sensitivity to the TMPRSS2 inhibitor Nafamostat. As with BA.1, we observed BA.5 to significantly reduce neutralisation titres across all donors. Concentrated pooled human IgG from convalescent and vaccinated donors had greater breadth of neutralisation, although the potency was still reduced 7-fold with BA.5. Of all therapeutic antibodies tested, we observed a 14.3-fold reduction using Evusheld and 16.8-fold reduction using Sotrovimab when neutralising a Clade A versus BA.5 isolate. These results have implications for ongoing tracking and management of Omicron waves globally.

Introduction

At the beginning of November 2021, the VOC Omicron BA.1 surged globally with close to 4 million infections per day reported by mid-January. This variant was then supplanted by the genetically divergent BA.2 variant, which represented over 80% of cases reported worldwide by mid-April of 2022. In June 2022, three lineages derived from BA.2 were starting to dominate (. These included BA.2.12.1, BA.4 and BA.5. BA.4 and BA.5 share amino acid substitutions (compared to BA.2) L452R, F486V, and R493Q in the Spike receptor binding domain (RBD) whereas BA.2.12.1 is the only variant with the L452Q change. Across several areas globally, BA.5 is spreading preferentially over BA.2.12.1 and BA.4. The determinants of preferential spread are complex and must take into account many variables, including the prevalence of infection and/or vaccine coverage and the time from that latter antigenic exposure. In addition to the population level of immunity, the mechanism of viral entry and changes thereof may significantly influence viral tropism and subsequent disease severity even within previously vaccinated populations. For instance, the Delta variant had significant tropism for the ACE2-TMPRSS2 pathway and this pathway is associated with infection of the lung and disease severity in animal models 1-6. In contrast, Omicron BA.1 diverged from this pathway with a tropism trajectory towards the upper respiratory tract 3. The mechanism for Omicron favouring the upper respiratory tract is presently hypothesised to be the switch from TMPRSS2 to another serine or cysteine protease either present at the plasma membrane or enriched within the endolysosomal compartment 3,7-9. Whilst BA.2 has similar tropism to BA.1, recent studies on BA.5 and related lineages bearing L452 polymorphisms highlight a shift in tropism back to pre-Omicron lineages, with potential increase in disease severity and infection within lung tissue observed in animal models (doi: https://doi.org/10.1101/2022.05.26.493539).

Recently we developed a rapid and sensitive platform for the isolation and characterisation of SARS-CoV-2 variants with respect to their relative transmission threat in previously infected and vaccinated populations 7. This platform rapidly feeds back three key observations with respect to early characterisation of viral variants in primary nasopharyngeal samples. Firstly, it enables neutralisation studies on primary clinical viral isolates. Secondly, it determines which immunotherapeutics retain potency. Finally, it can resolve subtle changes in tropism towards or away from from the ACE2-TMPRSS2 pathway of primary clinical isolates by the increase or decrease of the viral infectivity to particle ratio. In the latter setting, this system could not only map increase usage of TMPRSS2 by Delta in primary nasopharyngeal swabs, but also readily demonstrate the decreased use of TMPRSS2 by Omicron BA.1. As this can be done with diagnostic primary samples, it can reveal tropism changes when a variant starts expanding within a community in real time.

Through using individual serum samples from 74 patients recruited to ADAPT10, a community-based cohort of approximately 200 patients followed from the time of diagnosis during all waves of infection in Australia, we tested a continuum of responses ranging from triple vaccinated donors, convalescent donors post vaccination and Omicron breakthrough infections of triple vaccinated individuals. To assess breadth across variants, we tested live virus neutralisation potency against the pre-Omicron clades A2.2, Beta and Delta alongside the Omicron lineages BA.1, BA.2 and BA.5. We then tested 13 polyclonal human hyperimmune IgG batches that constitute pools of thousands of primarily US plasma donors collected in late 2021 prior to the onset of the global Omicron BA.1 wave (Figure 1E). This latter analysis establishes the extent of immune evasion at the population level at that time period, as the IgG is comprised of all plasma donors irrespective if they are convalescent and/or vaccinated. Alongside patient sera, we also tested clinical grade Xevudy (sotrovimab) and Evusheld (tixagevimab and cilgavimab) for changes in potency across all above listed variants. Finally, with overlapping waves of BA.2 and BA.5 infection within Australia at the time of writing, we then determined the infectivity to particle ratios of virus within primary nasopharyngeal swabs and furthermore established the mode of entry of BA5 versus other Omicron and pre-Omicron lineages.