30 April Update on XBB variants 1.9 and 1.16

Episode 331:  What to expect of newly emerging variants XBB.1.9 and XBB.1.16

Dear colleagues,

The prediction that the recombinant XBB.1.5 variant was going to conquer the world during this winter, as explained in Ep 304 (5 Jan 2023), came true.  But, as could be expected the virus shows further evolution towards increased transmissibility and immune escape.  Over the last few months, new XBB variants are on the rise.  What is their present and expected impact?  

Ep 331-1: CDC COVID Data Tracker 29-4-2023

Ep 331-2 : WHO 27 April  2023: Tracking SARS-CoV-2 variants

All three are recombinants of BA.2.10.1 and BA.2.75 sublineages,

They are based on XBB.1 with few additional Spike mutations

XBB.1.9.1            = XBB.1 + Spike S486P (= similar to XBB.1.5)

XBB.1.9.2            = XBB.1 + Spike F486P + Q613H

XBB.1.16             = XBB.1 + Spike E180V; K478R and F486P

Ep 331-3: Sciensano 28 April Molecular surveillance p. 14

In Belgium, XBB.1.5 is decreasing, while XBB.1.9 is increasing during the month of April

Ep 331-1: CDC COVID Data Tracker 29-4-2023

In US XBB.1.5 is still dominant > XBB.1.16 > XBB.1.9.1 > XBB.1.9.2

Ep 331-4: WHO Weekly Report of 27 April 2023 provides a nice summary

Globally, cases and deaths are at the lowest levels since the start of the pandemic.

However, there are important regional differences with a very clear to dramatic increases in the Eastern-Mediterranean and South-Eastern region (but also some increase in some Western-European, African and South-American countries).

With regard to global evolution of variants: XBB.1.5 is still the most prevalent, but declining and being replaced by other XBB sublineages, including XBB.1.9 and XBB.1.16.

Ep 331-5:  UK Health Security Agency Technical Briefing nr 51  10 March

XBB.1.9.1 is rapidly increasing in proportion and is currently the only lineage with a significant growth advantage relative to XBB.1.5

XBB.1.9.2 is also increasing as a proportion of the samples in the UK, this lineage has acquired Spike R408S, F486P; ORF8:G8*; ORF1ab:G1819S, S5360P.

XBB.1.16 is a lineage with 3 additional spike mutations (E180V, K478R, and S486P)

Ep 331-6:  UK Health Security Agency Technical Briefing nr 52   21 April

Both XBB.1.9.1 and XBB.1.16 have clear growth advantage over XBB.1.5

• XBB.1.16 arose in India in Feb, where it has become dominant
• Also prevalent in Brunei, Singapore and Japan
• Low levels in US, Canada, Australia and New Zealand.

Ep 331-7 WHO Risk assessment 17 April: XBB.1.16 has growth advantage and immune escape, but NO signal of increased severity

Ep 331-8: Daichi Yamasoba bioRxiv 6 April 2023: Virological characteristics of XBB.1.16

XBB.1.16 has

• (A) Several non-Spike mutations over other XBB (which may explain higher fitness, despite similar in vitro infectivity and similar resistance to neutralization)
• (B) Clear growth advantage in India
• (C) Higher reproductive number than XBB.1 and XBB.1.5
• (D) Higher affinity for ACE-2 than XBB.1.5, but lower than XBB.1
• (E) Similar in vitro infectivity
• (F-G) Strong immune escape from human sera of vaccinated subjects, who had either a BA.2 or BA.5 breakthrough infection (similar escape as XBB.1 and XBB.1.5)
• (H) However, sera from hamsters infected with XBB.1.1 neutralize XBB.1.5 and XBB.1.16 equally well.
• (I) Hence, XBB.1.1, XBB.1.5 and XBB.1.16 constitute a separate cluster in principle component analysis : a different “serotype” from  previous SARS-CoV-2 strains e.g. B.1 (= Wuhan) as well as Omicron BA.2 and BA.5.

(A) Frequency of mutations of interest in the representative XBB sublineages.

(B) Estimated epidemic dynamics of XBB sublineages in India from Oct 1 2022 to March 5, 2023.

(C) Estimated relative Re  (reproductive number) of the representative XBB sublineages. The relative Re of XBB.1 is set to 1 (horizontal dashed line).

(D) The dissociation constant (KD) value indicating the binding affinity of the RBD of the SARS-CoV-2 S protein to soluble ACE2 when expressed on yeast is shown. The horizontal dashed line indicates the mean KD value of the RBD of the XBB.1.

(E)The percentage infectivity of XBB.1, XBB.1.5+E180V

(XBB.1+S:F486P/E180V), XBB.1.5+T478R (XBB.1+S:F486P/T478R), and XBB.1.16 (XBB.1+S:F486P/E180V/T478R) compared to that of XBB.1.5 are shown. Red and blue asterisks, respectively, indicate decreased and

increased percentage infectivity. NS, no statistical significance.

(F-H) Neutralization assay. Assays were performed with pseudoviruses harboring the S proteins of B.1.1, BA.2, BA.5, XBB.1, XBB.1.5 (XBB.1+S:F486P), XBB.1.5+E180V (XBB.1+S:F486P/E180V), XBB.1.5+T478R (XBB.1+S:F486P/T478R), and XBB.1.16 (XBB.1+S:F486P/E180V/T478R).

The following sera were used:

F and G: Convalescent sera from fully vaccinated individuals who had a breakthrough infection with BA.2 (F) and those who had been infected with BA.5 after full vaccination (G)

and sera from hamsters infected with XBB.1 ( (H) were used.

(I) Principal component (PC) analysis representing the antigenicity of the S proteins. The analysis is based on the results of neutralization assays using BA.2 and BA.5 breakthrough infection sera and XBB.1-infected hamster’s sera (F–H).

Of all therapeutic mAbs, only Sotrovimab has a reasonable neutralization capacity:

• About 5 times weaker than against B.1.1 (= Wuhan)
• But 4 times better than against BA.2 and BA.5

Ep 331-9: Rajesh Karyakarte medRxiv 26 April: Characteristics of XBB.1.16 in India

A very nice study, providing lots of details on the distribution and clinical characteristics of XBB.1.16 cases in India, with a special focus on Mahrashtra, with the highest prevalence

Gujarat

Maharashtra

Clinical features and outcome of XBB.1.16 were similar as for other co-circulating variants

But certainly not completely innocent: mortality present in youngest and oldest patients with co-morbidities

Provides also a very comprehensive overview Venn diagram of mutations in XBB.1.5, XBB.1.9 and XBB.1.16

Ep 311-10: Vipin Vashishtha medRxiv 20 April Clinical characteristics in children infected with XBB.1.16

• Mild febrile illness in children in India
• Young infants are disproportionately more affected than older children.
• Respiratory symptoms are predominating (while in previous waves more GI symptoms were seen .
• Itchy non-purulent conjunctivitis is seen in 42.8% of affected infants. No marked redness (as seen in otherv  viral conjuctivites such as with adenoviruses, measles, influenza or RSV).

Ep 331-11: Martina Zappa Eur J Int Med 17 April speculate that XBB.1.16 is an example of how the pandemic evolves suggesting  that we are probably approaching a post-epidemic era.

The SARS-CoV-2 variants are continuing to evolve and survive, but the virulence of infection associated with novel strains may stabilize at lower levels, as result of the evolutionary changes, when compared to previous strains.

In any case, tracking SARS-CoV-2 variants remains mandatory and the effects of COVID-19 restrictions and vaccination on the evolution of the virus remain to be fully elucidated.

They also provide a nice model of XBB.1.16 Spike

Conclusion: The new XBB variants 1.9 and 1.16 display a competitive advantage in the epidemic towards older XBB (including 1.5). 

• During late April XBB.1.9 is on the rise in Belgium, but XBB.1.16 has not yet been reported. XBB.1.16 is mainly prevalent in countries of South-East Asia (India, Brunei, Singapore) and in Japan.  In the US and UK, both XBB.19 and XBB.1.16 are on the rise.
• Mutations in Spike are probably not the sole explanation for the rapid spread of XBB.1.9 and XBB.1.16 , as the in vitro infectivity and the immune escape characteristics are similar across XBB variants. The role of mutations in other ORF has not yet been analyzed.
• According to reports from India, on clinical characteristics of XBB.1.16 are similar to previous variants: the disease is not more severe, but deaths do occur in children under 10 and elderly with co-morbidities. Some particular signs have been seen in young children: a mild respiratory disease with a “typical” non-purulent conjunctivitis.
• Sotrovimab is the only therapeutic monoclonal that keeps a reasonable activity against the XBB variants, better than against BA.2 and BA.5, but it is less potent than against the original B.1.1 strain
• The hamster experiment showing that infection with XBB.1.1 induces neutralizing antibodies against XBB.1.5 and XBB.1.16, suggests that the XBB.1.1 Spike may have potential as a “pan-XBB” vaccine.
• Whether COVID becomes a really “mild” disease remains uncertain.  The evolution of the death rate is mixed over the globe with decreasing or increasing trends sometimes in neighboring countries of different continents.  However the very significantly rising death rates in South-East Asia (where the new XBB’s are very prevalent) is worrying.

Best wishes,

Guido