SARS-CoV-2 variant rapid risk assessment report: XBB.1.5

Transmissibility

• XBB.1.5 is a sub-lineage of the SARS-CoV-2 lineage XBB.1, a recombinant of Omicron variants BA.2.10^{Table 2 Footnote *} and BA.2.75^{Table 2 Footnote *}. XBB.1.5 has acquired an additional mutation in the spike protein (Receptor Binding Domain mutation 486P). Thus, XBB.1.5 likely is more transmissible than XBB.1 because of the increased ACE2 affinity^{Footnote 1}.

International

• As of January 11, 2023, 5,288 sequences have been reported across 38 different countries. Most of these submissions are from the United States, but there are also increasing numbers of detections in Europe^{Footnote 2}.
• As of January 16, 2023, XBB.1.5 is estimated to have a growth advantage (~10% per day) over currently circulating lineages in North America and Europe. However, local growth estimates vary from ~10–20% per day relative to lineages circulating in those US states or EU countries^{Footnote 3}.
• From data posted on January 13, 2023, the US CDC estimates the current proportion of XBB.1.5 to be 11.5% for the week ending December 24, 2022. Projections for the week ending January 14, 2023, suggest XBB.1.5 will comprise 43.0% of sequences in the US. There is large geographic variation noted, with 2 regions in the northeastern US projecting that XBB.1.5 will comprise over 80% of sequences and 5 other regions projected at between 8-16% of sequences for the week ending January 14, 2023^{Footnote 4}.

Domestic

• As of January 16, 2023, there are 126 detections of XBB.1.5 in Canada reported to the Public Health Agency of Canada dating back to November 20, 2022. Most of them are reported from Ontario.
• Ontario has reported that the proportion of XBB.1.5 is increasing and that projected prevalence will be 22.2% by January 18, 2023. XBB.1.5 has been detected in multiple health regions^{Footnote 5}.
• By January 16, 2023, XBB.1.5 is projected to be 7% of sequences reported to the Public Health Agency of Canada.
• The overall growth advantage of this sub-lineage relative to all other currently circulating strains in Canada is ~ 9% per day (6-10%, 95% CI).

Disease severity

International

• The ECDC assessment of the XBB.1.5 sub-lineage stated that there is no indication that infections from XBB.1.5 differ in severity from currently circulating Omicron lineages^{Footnote 6}.
• The WHO reports that severity data is unavailable and assessments are ongoing. However, XBB.1.5 does not carry any mutation known to be associated with potential change in severity (such as S:P681R)^{Footnote 2}.
• According to the WHO TAG-VE, the early evidence as of October 27, 2022, does not suggest substantial differences in disease severity for XBB (and XBB sub-lineages) infections compared to other Omicron sub-lineages^{Footnote 7}.

Domestic

• As of January 12, 2023, there are 18 COVID-19 cases associated with XBB.1.5 in the national case surveillance database, with 4 hospitalizations, no ICU admissions, and no deaths.

Immune evasion^{Table 2 Footnote a}

Neutralizing antibody responses

• Currently, most studies evaluating immunity from a prior SARS-CoV-2 infection include individuals with hybrid immunity (immunity obtained from vaccination and SARS-CoV-2 infection), as a result there are fewer studies conducted on those who have only infection-acquired immunity.
• Preliminary in-vitro evidence suggests that XBB^{Table 2 Footnote *} sub-lineages are the most antibody-evasive SARS-CoV-2 sub-lineages identified to date and XBB.1.5 is shown to be similarly immune evasive as XBB.1 in 3 pre-prints. Two studies show that XBB.1.5 resists neutralizing immune responses from individuals with hybrid immunity (including prior BA.5 or BA.2 infection after 2-4 doses of monovalent mRNA vaccines)^{Footnote 1Footnote 8}. Additional data demonstrates XBB.1.5 resists neutralizing immune responses from individuals infected with BA.4/5 (most of whom were unvaccinated), vaccinated with 3 doses of the monovalent vaccine, and vaccinated with a bivalent booster after 2 to 4 monovalent doses (most received 3 monovalent doses)^{Footnote 9}.
• Nine additional studies have evaluated neutralization of XBB^{Table 2 Footnote *} variants by sera from individuals with 3 different immune backgrounds (vaccination and/or infection): (1) vaccinated with 3-4 doses of the original monovalent mRNA vaccine, (2) vaccinated with a bivalent booster, or (3) breakthrough infection with BA.2 or BA.4/5.
  • Evidence suggests that XBB^{Table 2 Footnote *} highly resists neutralizing immune responses induced either by the original monovalent mRNA vaccines or by a combination of vaccination and infection-derived immunity (i.e., hybrid immunity) to a greater degree than BA.5^{Footnote 10Footnote 11Footnote 12Footnote 13Footnote 14}
  • XBB^{Table 2 Footnote *} also resists neutralization to immunity induced by the bivalent boosters to a greater extent than BA.4/5^{Footnote 12Footnote 15Footnote 16Footnote 17Footnote 18}. However, most of these studies suggest bivalent boosters elicit somewhat higher neutralizing antibody titers against XBB^{Table 2 Footnote *} than a monovalent vaccine booster.

Cellular responses

• No studies assessing T-cell immunity are available for XBB.1.5 specifically. However, recent in-vitro studies suggest that CD8+ and CD4+ T-cell responses against XBB are largely conserved^{Footnote 19}.
• A pre-print retrospective study from Singapore evaluated the protective effectiveness (PE) of a previous SARS-CoV-2 infection among those who received monovalent mRNA vaccination (2-3 doses) against a BA.4/5 and XBB reinfection (specific sub-lineage not reported)^{Footnote 20}. PE against an XBB reinfection was lower than PE against BA.4/5 reinfection regardless of the prior infecting variant (PE from a prior BA.2 infection among those with 3 mRNA doses was 78% against a BA.4/5 infection versus 51% against XBB infection).

There is no data on vaccine effectiveness against XBB.1.5 infection or severe outcomes as well as no data on protective effectiveness from a prior infection against XBB-related severe outcomes.

Therapeutics

• Paxlovid (nirmatrelvir/ritonavir) and Remdesivir seem to retain their activity against SARS-CoV-2 Omicron^{Footnote 21}. It is unknown currently if the same holds true for the recombinant XBB.1.5.
• Limited in-vitro data on the activity of COVID-19 mAbs is available against XBB.1.5.
• A preprint listed on the Stanford University coronavirus antiviral and resistance database suggests that tixagevimab/cilgavimab (Evusheld) and sotrovimab have reduced or no activity against XBB.1.5^{Footnote 1}. They also demonstrate that XBB.1 and XBB.1.5 show comparable mAb evasion.
  • Sub-lineage group: XBB.1.5; mAbs tested: sotrovimab; viral type: pseudovirus; fold-change^{Table 2 Footnote b}: 1; reference strain: XBB.1; source: Yue et al.^{Footnote 1}
  • Sub-lineage group: XBB.1.5; mAbs tested: Tixagevimab/ cilgavimab: viral type: pseudovirus; fold-change^{Table 2 Footnote b}: 0.9; reference strain: XBB.1; source; Yue et al.^{Footnote 1}
• In an in-vitro study, Evusheld and Sotrovimab had decreased in activity against XBB compared to BA.5^{Footnote 22}. Evusheld and Sotrovimab may not be effective against XBB.1 and XBB when compared to the ancestral (original) SARS-CoV-2 strain^{Footnote 11}.
• The product monograph for Evusheld reports a reduction in susceptibility to XBB compared to BA.5.
• No Canadian in-vitro data is available on the activity of COVID-19 antivirals against XBB.1.5.
• No Canadian data on the clinical effectiveness of COVID-19 therapeutics (antivirals or monoclonal antibodies [mAbs]) is available for XBB.1.5.

Considerations

• The U.S. Food and Drug Administration (PDF) defines 'no change' in in-vitro activity for mAbs in its authorized fact sheet guidance documents as <5-fold reduction in susceptibility
• Since in-vitro assays are often conducted under controlled conditions, they do not reflect the in-vivo pharmacokinetic properties of the therapeutic under investigation. Therefore, in-vitro studies do not correlate with therapeutic effectiveness or treatment failure.

Health systems impact, including hospital capacity and infection prevention and control measures
(Capacity: beds, health care workers)

• Hospital and health care capacity in Canada remains strained due to circulating influenza, RSV, and SARS-CoV-2 and other pressures. Infection, prevention and control practices are in place to limit transmission of COVID-19.

Border measures
(Vaccination, quarantine and testing)

• Border measures are designed to slow the importation of new variants, while XBB.1.5 has been detected in Canada since November 2022.

Surveillance capacity

• Wastewater assays in Canada can detect XBB.1.5.
• Confirmatory testing volumes have remained relatively stable, but outpatient testing is generally restricted to specific populations and symptomatic patients. Asymptomatic testing is primarily for at-risk populations, including individuals at risk of severe outcomes, and their contacts. As such, surveillance data are not representative of all COVID-19 infections in Canada.
• Testing and sequencing strategies may differ across the country.

Public health measures

• The current Public Health Agency of Canada guidance on public health measures includes the layered use of individual public health measures such as staying home when ill, properly wearing a well-constructed and well-fitting mask in public indoor settings, improving indoor ventilation, performing frequent hand hygiene and proper respiratory etiquette, and cleaning and disinfecting high-touch surfaces and objects, to reduce the risk of infection and spread.
• Public health measures recommendations in Canada continue to vary across jurisdictions as provinces and territories experience differing epidemiology and risks as well as transition to the longer-term management of COVID-19.
• Most community-based measures such as lockdowns, widespread case and contact management activities, including quarantine and isolation requirements as well as universal masking have ended. Individual risk-based measures are being promoted (e.g., staying home when ill, wearing a mask in certain circumstances, etc.).

Vaccination

• As of January 1, 2023 (most recent available data), 80.6% of the total population has completed a primary series of COVID-19 vaccine.
• As of January 1, 2023 (most recent available data), 25.0% of the total population have completed their primary series or received a booster dose of COVID-19 vaccine in the last six months^{Footnote 23}.