Pathogenicity and transmissibility of bovine H5N1 influenza virus.

Highly pathogenic H5N1 avian influenza (HPAI H5N1) viruses occasionally infect, but typically do not transmit, in mammals. In the Spring of 2024, an unprecedented outbreak of HPAI H5N1 in bovine herds occurred in the US, with virus spread within and between herds, infections in poultry and cats, and spillover into humans, collectively indicating an increased public health risk1-4. Here, we characterized an HPAI H5N1 virus isolated from infected cow milk in mice and ferrets. Like other HPAI H5N1 viruses, the bovine H5N1 virus spread systemically, including to the mammary glands of both species; however, this tropism was also observed for an older HPAI H5N1 virus isolate. Importantly, bovine HPAI H5N1 virus bound to sialic acids expressed in human upper airways and inefficiently transmitted to exposed ferrets (one of four exposed ferrets seroconverted without virus detection). Bovine HPAI H5N1 virus thus possesses features that may facilitate infection and transmission in mammals.

Safety and immunogenicity of the intranasal H3N2 M2-deficient single-replication influenza vaccine alone or coadministered with an inactivated influenza vaccine (Fluzone High-Dose Quadrivalent) in adults aged 65-85 years in the USA: a multicentre, randomised, double-blind, double-dummy, phase 1b trial.

BACKGROUND: Older adults (aged ≥65 years) show increased susceptibility to severe disease with influenza virus infection, accounting for 70-85% of annual influenza-related fatalities in the USA. Stimulating mucosal antibodies and T cells might enhance the low vaccine effectiveness seen in older adults for currently licensed inactivated influenza vaccines, which induce mainly serum antibodies. We aimed to evaluate the safety and immunogenicity of the intranasal H3N2 M2-deficient single-replication (M2SR) vaccine, alone or coadministered with a licensed inactivated influenza vaccine (Fluzone High-Dose Quadrivalent; hereafter referred to as Fluzone HD), in older adults. METHODS: In this multicentre, randomised, double-blind, double-dummy, phase 1b trial, individuals aged 65-85 years who were considered healthy or with stable chronic conditions with no recent (<6 months) influenza vaccinations were recruited from five clinical trial sites in the USA and randomly assigned (3:3:3:1) using a permuted block design to receive the H3N2 M2SR vaccine and Fluzone HD, the H3N2 M2SR vaccine and placebo, Fluzone HD and placebo, or placebo alone. All participants received a single intranasal spray and a single intramuscular injection, whether active or placebo, to maintain masking. The primary outcome was to assess the safety of H3N2 M2SR, administered alone or with Fluzone HD, in the safety analysis set, which included all participants who were randomly assigned and received treatment. Serum and mucosal antibodies were assessed as a secondary endpoint, and cell-mediated immunity as an exploratory endpoint, in participants in the per-protocol population, which included individuals in the safety analysis set without major protocol deviations. This trial is registered with ClinicalTrials.gov, NCT05163847. FINDINGS: Between June 14 and Sept 15, 2022, 305 participants were enrolled and randomly assigned to receive the H3N2 M2SR vaccine plus placebo (n=89), H3N2 M2SR vaccine plus Fluzone HD (n=94), Fluzone HD plus placebo (n=92), or placebo alone (n=30). All randomly assigned participants were included in the safety analysis set. The most frequently reported local symptoms up to day 8 in groups that received M2SR were rhinorrhoea (43% [38 of 89] in the H3N2 M2SR plus placebo group and 38% [36 of 94] in the H3N2 M2SR plus Fluzone HD group), nasal congestion (51% [45 of 89] and 35% [33 of 94]), and injection-site pain (8% [seven of 89] and 49% [46 of 94]), and the most frequently reported solicited systemic symptoms were sore throat (28% [25 of 89]) for M2SR and decreased activity (26% [24 of 94]) for the M2SR plus Fluzone HD group. In the Fluzone HD plus placebo group, the most frequently reported local symptom was injection-site pain (48% [44 of 92]) and systemic symptom was muscle aches (22% [20 of 92]). The frequency of participants with any treatment-emergent adverse event related to vaccination was low across all groups (2-5%). One serious adverse event was reported, in a participant in the Fluzone HD plus placebo group. M2SR with Fluzone HD induced seroconversion (≥four-fold increase in haemagglutination inhibition antibodies from baseline to day 29) in 44 (48%) of 91 participants, compared with 28 (31%) of 90 participants who seroconverted in the Fluzone HD plus placebo group (p=0·023). M2SR with Fluzone HD also induced mucosal and cellular immune responses. INTERPRETATION: The H3N2 M2SR vaccine coadministered with Fluzone HD in older adults was well tolerated and provided enhanced immunogenicity compared with Fluzone HD administered alone, suggesting potential for improved efficacy of influenza vaccination in this age group. Additional studies are planned to assess efficacy. FUNDING: US Department of Defense.

Antiviral susceptibility of SARS-CoV-2 and influenza viruses from 3 co-infected pediatric patients.

In Japan, influenza activity was low throughout the COVID-19 pandemic until the 2022-23 season, when the first influenza outbreak occurred since the 2020-21 season. In our influenza surveillance during the COVID-19 pandemic, co-infection with SARS-CoV-2 and influenza virus had not been detected; however, in January 2024, we identified three pediatric outpatients co-infected with these viruses: one with SARS-CoV-2 Omicron EG.5 sublineage HK.3 and influenza A(H3N2) and two with SARS-CoV-2 Omicron BA.2.86 sublineage JN.1.5 and influenza A(H1N1)pdm09. We evaluated the susceptibility of SARS-CoV-2 against RNA-dependent RNA polymerase inhibitors (remdesivir and molnupiravir) and 3C-like protease inhibitors (nirmatrelvir and ensitrelvir), and that of influenza viruses against neuraminidase inhibitors (oseltamivir, peramivir, zanamivir, and laninamivir) and the cap-dependent endonuclease inhibitor baloxavir. All viruses tested were susceptible to these antiviral drugs and did not possess amino acid substitutions associated with reduced antiviral susceptibility. The patients were treated with anti-influenza drugs and did not develop severe symptoms despite the co-infection. Since SARS-CoV-2 and influenza viruses continue to evolve, continuous monitoring of their circulation remains essential to assess public health measures and support clinical management.

Monitoring Influenza C and D Viruses in Patients With Respiratory Diseases in Japan, January 2018 to March 2023.

BACKGROUND: Influenza viruses can cause zoonotic infections that pose public health risks. Surveillance of influenza A and B viruses is conducted globally; however, information on influenza C and D viruses is limited. Longitudinal monitoring of influenza C virus in humans has been conducted in several countries, but there has been no long-term monitoring of influenza D virus in humans. The public health risks associated with the influenza D virus therefore remain unknown. METHODS: We established a duplex real-time RT-PCR to detect influenza C and D viruses and analyzed respiratory specimens collected from 2144 patients in Japan with respiratory diseases between January 2018 and March 2023. We isolated viruses and conducted hemagglutination inhibition tests to examine antigenicity and focus reduction assays to determine susceptibility to the cap-dependent endonuclease inhibitor baloxavir marboxil. RESULTS: We detected three influenza C viruses belonging to the C/Kanagawa- or C/Sao Paulo-lineages, which recently circulated globally. None of the specimens was positive for the influenza D virus. The C/Yokohama/1/2022 strain, isolated from the specimen with the highest viral RNA load and belonging to the C/Kanagawa-lineage, showed similar antigenicity to the reference C/Kanagawa-lineage strain and was susceptible to baloxavir. CONCLUSIONS: Our duplex real-time RT-PCR is useful for the simultaneous detection of influenza C and D viruses from the same specimen. Adding the influenza D virus to the monitoring of the influenza C virus would help in assessing the public health risks posed by this virus.

SARS-CoV-2 incidence, seroprevalence, and antibody dynamics in a rural, population-based cohort: March 2020 - July 2022.

Studies of SARS-CoV-2 incidence are important for response to continued transmission and future pandemics. We followed a rural community cohort with broad age representation with active surveillance for SARS-CoV-2 identification from November 2020 through July 2022. Participants provided serum specimens at regular intervals and following SARS-CoV-2 infection or vaccination. We estimated the incidence of SARS-CoV-2 infection identified by study RT-PCR, electronic health record documentation or self-report of a positive test, or serology. We also estimated the seroprevalence of SARS-CoV-2 spike and nucleocapsid antibodies measured by ELISA. Overall, 65% of the cohort had ≥1 SARS-CoV-2 infection by July 2022, and 19% of those with primary infection were reinfected. Infection and vaccination contributed to high seroprevalence, 98% (95% CI: 95%, 99%) of participants were spike or nucleocapsid seropositive at the end of follow-up. Among those seropositive, 82% were vaccinated. Participants were more likely to be seropositive to spike than nucleocapsid following infection. Infection among seropositive individuals could be identified by increases in nucleocapsid, but not spike, ELISA optical density values. Nucleocapsid antibodies waned more quickly after infection than spike antibodies. High levels of SARS-CoV-2 population immunity, as found in this study, are leading to changing epidemiology necessitating ongoing surveillance and policy evaluation.

Comparative analysis of SARS-CoV-2 neutralization titers reveals consistency between human and animal model serum and across assays.

The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires ongoing monitoring to judge the ability of newly arising variants to escape the immune response. A surveillance system necessitates an understanding of differences in neutralization titers measured in different assays and using human and animal serum samples. We compared 18 datasets generated using human, hamster, and mouse serum and six different neutralization assays. Datasets using animal model serum samples showed higher titer magnitudes than datasets using human serum samples in this comparison. Fold change in neutralization of variants compared to ancestral SARS-CoV-2, immunodominance patterns, and antigenic maps were similar among serum samples and assays. Most assays yielded consistent results, except for differences in fold change in cytopathic effect assays. Hamster serum samples were a consistent surrogate for human first-infection serum samples. These results inform the transition of surveillance of SARS-CoV-2 antigenic variation from dependence on human first-infection serum samples to the utilization of serum samples from animal models.

Development of a Mouse-Adapted Reporter SARS-CoV-2 as a Tool for Two-Photon In Vivo Imaging.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) often causes severe viral pneumonia. Although many studies using mouse models have examined the pathogenicity of SARS-CoV-2, COVID-19 pathogenesis remains poorly understood. In vivo imaging analysis using two-photon excitation microscopy (TPEM) is useful for elucidating the pathology of COVID-19, providing pathological insights that are not available from conventional histological analysis. However, there is no reporter SARS-CoV-2 that demonstrates pathogenicity in C57BL/6 mice and emits sufficient light intensity for two-photon in vivo imaging. Here, we generated a mouse-adapted strain of SARS-CoV-2 (named MASCV2-p25) and demonstrated its efficient replication in the lungs of C57BL/6 mice, causing fatal pneumonia. Histopathologic analysis revealed the severe inflammation and infiltration of immune cells in the lungs of MASCV2-p25-infected C57BL/6 mice, not unlike that observed in COVID-19 patients with severe pneumonia. Subsequently, we generated a mouse-adapted reporter SARS-CoV-2 (named MASCV-Venus-p9) by inserting the fluorescent protein-encoding gene Venus into MASCV2-p25 and sequential lung-to-lung passages in C57BL/6 mice. C57BL/6 mice infected with MASCV2-Venus-p9 exhibited severe pneumonia. In addition, the TPEM of the lungs of the infected C57BL/6J mice showed that the infected cells emitted sufficient levels of fluorescence for easy observation. These findings suggest that MASCV2-Venus-p9 will be useful for two-photon in vivo imaging studies of the pathogenesis of severe COVID-19 pneumonia.

Ipsilateral and contralateral coadministration of influenza and COVID-19 vaccines produce similar antibody responses.

BACKGROUND: World Health Organisation (WHO) and USA Centers for Disease Control and Prevention (U.S. CDC) recommendations now allow simultaneous administration of COVID-19 and other vaccines. We compared antibody responses after coadministration of influenza and bivalent COVID-19 vaccines in the same (ipsilateral) arm vs. different (contralateral) arms. METHODS: Pre- and post-vaccination serum samples from individuals in the Prospective Assessment of COVID-19 in a Community (PACC) cohort were used to conduct haemaglutination inhibition (HI) assays with the viruses in the 2022-2023 seasonal influenza vaccine and focus reduction neutralisation tests (FRNT) using a BA.5 SARS-CoV-2 virus. The effect of ipsilateral vs. contralateral vaccination on immune responses was inferred in a model that accounted for higher variance in vaccine responses at lower pre-vaccination titers. FINDINGS: Ipsilateral vaccination did not cause higher influenza vaccine responses compared to contralateral vaccination. The response to SARS-CoV-2 was slightly increased in the ipsilateral group, but equivalence was not excluded. INTERPRETATION: Coadministration of influenza and bivalent COVID-19 vaccines in the same arm or different arms did not strongly influence the antibody response to either vaccine. FUNDING: This work was supported by the U.S. CDC (grant number: 75D30120C09259).

A compendium of multi-omics data illuminating host responses to lethal human virus infections.

Human infections caused by viral pathogens trigger a complex gamut of host responses that limit disease, resolve infection, generate immunity, and contribute to severe disease or death. Here, we present experimental methods and multi-omics data capture approaches representing the global host response to infection generated from 45 individual experiments involving human viruses from the Orthomyxoviridae, Filoviridae, Flaviviridae, and Coronaviridae families. Analogous experimental designs were implemented across human or mouse host model systems, longitudinal samples were collected over defined time courses, and global multi-omics data (transcriptomics, proteomics, metabolomics, and lipidomics) were acquired by microarray, RNA sequencing, or mass spectrometry analyses. For comparison, we have included transcriptomics datasets from cells treated with type I and type II human interferon. Raw multi-omics data and metadata were deposited in public repositories, and we provide a central location linking the raw data with experimental metadata and ready-to-use, quality-controlled, statistically processed multi-omics datasets not previously available in any public repository. This compendium of infection-induced host response data for reuse will be useful for those endeavouring to understand viral disease pathophysiology and network biology.

Characterization of Omicron BA.4.6, XBB, and BQ.1.1 subvariants in hamsters.

During the Omicron wave, previous variants such as BA.2, BA.4, and BA.5 were replaced by newer variants with additional mutations in the spike protein. These variants, BA.4.6, BQ.1.1, and XBB, have spread in different countries with different degrees of success. Here, we evaluated the replicative ability and pathogenicity of BA.4.6, BQ1.1, and XBB clinical isolates in male Syrian hamsters. Although we found no substantial differences in weight change among hamsters infected with these Omicron subvariants, the replicative ability of BQ.1.1 and XBB in lung tissue was higher than that of BA.4.6 and BA.5. Of note, BQ.1.1 was lethal in both male and female transgenic human ACE2 hamsters. In competition assays, XBB replicated better than BQ.1.1 in the nasal turbinate tissues of female hamsters previously infected with Omicron BA.2. These results suggest that newer Omicron subvariants in the XBB family are still evolving and should be closely monitored.

Mucosal immunization with dual influenza/COVID-19 single-replication virus vector protects hamsters from SARS-CoV-2 challenge.

The COVID-19 pandemic has highlighted the need for mucosal vaccines as breakthrough infections, short-lived immune responses and emergence of new variants have challenged the efficacy provided by the first generation of vaccines against SARS-CoV-2 viruses. M2SR SARS-CoV-2, an M2-deleted single-replication influenza virus vector modified to encode the SARS-CoV-2 receptor binding domain, was evaluated following intranasal delivery in a hamster challenge model for protection against Wuhan SARS-CoV-2. An adjuvanted inactivated SARS-CoV-2 whole virus vaccine administered intramuscularly was also evaluated. The intranasal M2SR SARS-CoV-2 was more effective than the intramuscular adjuvanted inactivated whole virus vaccine in providing protection against SARS-CoV-2 challenge. M2SR SARS-CoV-2 elicited neutralizing serum antibodies against Wuhan and Omicron SARS-CoV-2 viruses in addition to cross-reactive mucosal antibodies. Furthermore, M2SR SARS-CoV-2 generated serum HAI and mucosal antibody responses against influenza similar to an H3N2 M2SR influenza vaccine. The intranasal dual influenza/COVID M2SR SARS-CoV-2 vaccine has the potential to provide protection against both influenza and COVID.

Avian H6 Influenza Viruses in Vietnamese Live Bird Markets during 2018-2021.

Avian influenza viruses of the H6 subtype are prevalent in wild ducks and likely play an important role in the ecology of influenza viruses through reassortment with other avian influenza viruses. Yet, only 152 Vietnamese H6 virus sequences were available in GISAID (Global Initiative on Sharing All Influenza Data) prior to this study with the most recent sequences being from 2018. Through surveillance in Vietnamese live bird markets from 2018 to 2021, we identified 287 samples containing one or several H6 viruses and other influenza A virus subtypes, demonstrating a high rate of co-infections among birds in Vietnamese live bird markets. For the 132 H6 samples with unique influenza virus sequences, we conducted phylogenetic and genetic analyses. Most of the H6 viruses were similar to each other and closely related to other H6 viruses; however, signs of reassortment with other avian influenza viruses were evident. At the genetic level, the Vietnamese H6 viruses characterized in our study encode a single basic amino acid at the HA cleavage site, consistent with low pathogenicity in poultry. The Vietnamese H6 viruses analyzed here possess an amino acid motif in HA that confers binding to both avian- and human-type receptors on host cells, consistent with their ability to infect mammals. The frequent detection of H6 viruses in Vietnamese live bird markets, the high rate of co-infections of birds with different influenza viruses, and the dual receptor-binding specificity of these viruses warrant their close monitoring for potential infection and spread among mammals.

Tracing the origin of SARS-CoV-2 omicron-like spike sequences detected in an urban sewershed: a targeted, longitudinal surveillance study of a cryptic wastewater lineage.

BACKGROUND: The origin of novel SARS-CoV-2 spike sequences found in wastewater, without corresponding detection in clinical specimens, remains unclear. We sought to determine the origin of one such cryptic wastewater lineage by tracking and characterising its persistence and genomic evolution over time. METHODS: We first detected a cryptic lineage, WI-CL-001, in municipal wastewater in Wisconsin, USA, in January, 2022. To determine the source of WI-CL-001, we systematically sampled wastewater from targeted sub-sewershed lines and maintenance holes using compositing autosamplers. Viral concentrations in wastewater samples over time were measured by RT digital PCR. In addition to using metagenomic 12s rRNA sequencing to determine the virus's host species, we also sequenced SARS-CoV-2 spike receptor binding domains, and, where possible, whole viral genomes to identify and characterise the evolution of this lineage. FINDINGS: We traced WI-CL-001 to its source at a single commercial building. There we detected the cryptic lineage at concentrations as high as 2·7 × 109 genome copies per L. The majority of 12s rRNA sequences detected in wastewater leaving the identified source building were human. Additionally, we generated over 100 viral receptor binding domain and whole-genome sequences from wastewater samples containing the cryptic lineage collected over the 13 consecutive months this virus was detectable (January, 2022, to January, 2023). These sequences contained a combination of fixed nucleotide substitutions characteristic of Pango lineage B.1.234, which circulated in humans in Wisconsin at low levels from October, 2020, to February, 2021. Despite this, mutations in the spike gene and elsewhere resembled those subsequently found in omicron variants. INTERPRETATION: We propose that prolonged detection of WI-CL-001 in wastewater indicates persistent shedding of SARS-CoV-2 from a single human initially infected by an ancestral B.1.234 virus. The accumulation of convergent omicron-like mutations in WI-CL-001's ancestral B.1.234 genome probably reflects persistent infection and extensive within-host evolution. People who shed cryptic lineages could be an important source of highly divergent viruses that sporadically emerge and spread. FUNDING: The Rockefeller Foundation, Wisconsin Department of Health Services, Centers for Disease Control and Prevention, National Institute on Drug Abuse, and the Center for Research on Influenza Pathogenesis and Transmission.

Assessment of the antigenic evolution of a clade 6B.1 human H1N1pdm influenza virus revealed differences between ferret and human convalescent sera.

BACKGROUND: Influenza viruses continually acquire mutations in the antigenic epitopes of their major viral antigen, the surface glycoprotein haemagglutinin (HA), allowing evasion from immunity in humans induced upon prior influenza virus infections or vaccinations. Consequently, the influenza strains used for vaccine production must be updated frequently. METHODS: To better understand the antigenic evolution of influenza viruses, we introduced random mutations into the HA head region (where the immunodominant epitopes are located) of a pandemic H1N1 (H1N1pdm) virus from 2015 and incubated it with various human sera collected in 2015-2016. Mutants not neutralized by the human sera were sequenced and further characterized for their haemagglutination inhibition (HI) titers with human sera and with ferret sera raised to H1N1pdm viruses from 2009 to 2015. FINDINGS: The largest antigenic changes were conferred by mutations at HA amino acid position 187; interestingly, these antigenic changes were recognized by human, but not by ferret serum. H1N1pdm viruses with amino acid changes at position 187 were very rare until the end of 2018, but have become more frequent since; in fact, the D187A amino acid change is one of the defining changes of clade 6B.1A.5a.1 viruses, which emerged in 2019. INTERPRETATION: Our findings indicate that amino acid substitutions in H1N1pdm epitopes may be recognized by human sera, but not by homologous ferret sera. FUNDING: This project was supported by funding from the NIAID-funded Center for Research on Influenza Pathogenesis (CRIP, HHSN272201400008C).

Characterization of a human H3N8 influenza virus.

BACKGROUND: In 2022 and 2023, novel reassortant H3N8 influenza viruses infected three people, marking the first human infections with viruses of this subtype. METHODS: Here, we generated one of these viruses (A/Henan/4-10CNIC/2022; hereafter called A/Henan/2022 virus) by using reverse genetics and characterized it. FINDINGS: In intranasally infected mice, reverse genetics-generated A/Henan/2022 virus caused weight loss in all five animals (one of which had to be euthanized) and replicated efficiently in the respiratory tract. Intranasal infection of ferrets resulted in minor weight loss and moderate fever but no mortality. Reverse genetics-generated A/Henan/2022 virus replicated efficiently in the upper respiratory tract of ferrets but was not detected in the lungs. Virus transmission via respiratory droplets occurred in one of four pairs of ferrets. Deep-sequencing of nasal swab samples from inoculated and exposed ferrets revealed sequence polymorphisms in the haemagglutinin protein that may affect receptor-binding specificity. We also tested 90 human sera for neutralizing antibodies against reverse genetics-generated A/Henan/2022 virus and found that some of them possessed neutralizing antibody titres, especially sera from older donors with likely exposure to earlier human H3N2 viruses. INTERPRETATION: Our data demonstrate that reverse genetics-generated A/Henan/2022 virus is a low pathogenic influenza virus (of avian influenza virus descent) with some antigenic resemblance to older human H3N2 viruses and limited respiratory droplet transmissibility in ferrets. FUNDING: This work was supported by the Japan Program for Infectious Diseases Research and Infrastructure (JP23wm0125002), and the Japan Initiative for World-leading Vaccine Research and Development Centers (JP233fa627001) from the Japan Agency for Medical Research and Development (AMED).

Broad protection against clade 1 sarbecoviruses after a single immunization with cocktail spike-protein-nanoparticle vaccine.

The 2002 SARS outbreak, the 2019 emergence of COVID-19, and the continuing evolution of immune-evading SARS-CoV-2 variants together highlight the need for a broadly protective vaccine against ACE2-utilizing sarbecoviruses. While updated variant-matched formulations are a step in the right direction, protection needs to extend beyond SARS-CoV-2 and its variants to include SARS-like viruses. Here, we introduce bivalent and trivalent vaccine formulations using our spike protein nanoparticle platform that completely protect female hamsters against BA.5 and XBB.1 challenges with no detectable virus in the lungs. The trivalent cocktails elicit highly neutralizing responses against all tested Omicron variants and the bat sarbecoviruses SHC014 and WIV1. Finally, our 614D/SHC014/XBB trivalent spike formulation completely protects human ACE2-transgenic female hamsters against challenges with WIV1 and SHC014 with no detectable virus in the lungs. Collectively, these results illustrate that our trivalent protein-nanoparticle cocktail can provide broad protection against SARS-CoV-2-like and SARS-CoV-1-like sarbecoviruses.

Successful management of persistent COVID-19 using combination antiviral therapy (nirmatrelvir/ritonavir and remdesivir) and intravenous immunoglobulin transfusion in an immunocompromised host who had received CD20 depleting therapy for follicular lymphoma.

The management of persistent symptomatic coronavirus disease 2019 (COVID-19) infections in immunocompromised patients remains unclear. Here, we present the first case of successful antiviral therapy (nirmatrelvir/ritonavir and remdesivir) in combination with intravenous immunoglobulin (IVIg) in a patient who had received CD20 depleting therapy for follicular lymphoma and experienced recurrent COVID-19 relapses. After the patient received IVIg treatment, the viral load decreased without recurrence. Subsequently, it was found that the anti-spike antibody titer in the administered immunoglobulin was high at 9528.0 binding antibody units/mL. Our case highlights the potential of combination therapy with selective IVIg and antiviral drugs for relapsed immunocompromised COVID-19 patients who have received CD20 depleting therapy.

Clinical Efficacy of Imdevimab/Casirivimab for Persistent Omicron SARS-CoV-2 Infection in Patients with Hematological Malignancies.

Objective Prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been reported in immunocompromised patients, as they poorly develop antibodies against SARS-CoV-2. We conducted a clinical trial to determine the efficacy of Imdevimab/Casirivimab (Imde/Casiri), an anti-viral monoclonal antibody (mAb), for prolonged infection at our institution. Methods Nine patients with hematological malignancies (six with malignant lymphoma and three with multiple myeloma) in our institution presented with coronavirus disease 2019 caused by SARS-CoV-2 omicron variants (one, five, and one with BA.2, BA.5, and BF.7, respectively; two undetermined). Although not all nine patients developed severe disease, viral mRNA was detected in all patients after treatment with remdesivir or molnupiravir. Imde/casiri was infused 11-49 days after the disease onset. Results Within seven days of infusion, viral RNA was undetectable in five of the nine cases. Because all seven viruses isolated from patients whose viral RNA became undetectable showed low or no sensitivity to this monoclonal antibody cocktail, the disappearance of viral RNA in these cases may not be attributable to the antibody cocktail. Conclusion It may be worth considering the use of monoclonal antibodies that show some activity against these virus variants to treat persistent SARS-CoV-2 infection in immunocompromised patients.

An mRNA vaccine encoding the SARS-CoV-2 receptor-binding domain protects mice from various Omicron variants.

Here, we assessed the efficacy of a lipid nanoparticle-based mRNA vaccine candidate encoding the receptor-binding domain (LNP-mRNA-RBD) in mice. Mice immunized with LNP-mRNA-RBD based on the ancestral strain (ancestral-type LNP-mRNA-RBD) showed similar cellular responses against the ancestral strain and BA.5, but their neutralizing activity against BA.5 was lower than that against the ancestral strain. The ancestral-type LNP-mRNA-RBD protected mice from the ancestral strain or BA.5 challenge; however, its ability to reduce the viral burdens after BA.5 challenge was limited. In contrast, immunization with bivalent LNP-mRNA-RBD consisting of the ancestral-type and BA.4/5-type LNP-mRNA-RBD or monovalent BA.4/5-type LNP-mRNA-RBD elicited robust cellular responses, as well as high and moderate neutralizing titers against BA.5 and XBB.1.5, respectively. Furthermore, the vaccines containing BA.4/5-type LNP-mRNA-RBD remarkably reduced the viral burdens following BA.5 or XBB.1.5 challenge. Overall, our findings suggest that LNP-mRNA-RBD is effective against SARS-CoV-2 infection.