SARS-CoV-2 Omicron Variant Sub-Lineages BA.4 and BA.5: Evidence and ...

EVIDENCE BRIEF

SARS-CoV-2 Omicron Variant Sub-Lineages BA.4 and BA.5: Evidence and Risk Assessment (up to date as of June 23, 2022)

Published: June 27, 2022

Key Messages

The proportion of SARS-CoV-2 whole genome sequencing (WGS) samples identified as BA.4 and BA.5 is increasing in many jurisdictions, including Ontario, while the proportion of BA.2 and most BA.2 sub-lineages is declining. BA.5 and BA.4 are expected to soon become the dominant variants in Europe and the United States (US) and lead to increasing COVID-19 cases due to increased transmissibility and immune evasion.

In South Africa and Portugal, BA.5 and BA.4 waves peaked at 128.0 cases per million population (7-day moving average daily new confirmed COVID-19 cases) within three to four weeks of detection, with a test positivity rate of 25.47%.1 However, their epidemiology may not be generalizable to the Ontario context.

The weekly growth rates of BA.4 and BA.5 in Ontario are approximately 2.72 and 3.11 that of BA.2, respectively. In Ontario, BA.5 is projected to reach 52.9% of cases by June 29, 2022 and will likely increase the number of cases. The prevalence of BA.4 is projected to remain below 15%. Hospitalization and mortality are likely to increase due to the volume of cases, but there is uncertainty about the extent of the increase since the severity of BA.4 and BA.5 cases is unclear.

Among those eligible for molecular testing in Ontario, the number of positive cases continues to decline, however there are early signs of increasing positivity from wastewater surveillance programs and early evidence of plateauing test positivity.

Current COVID-19 vaccines and previous SARS-CoV-2 infection do not provide sterilizing immunity (i.e., full protection from infection or reinfection). Emerging evidence that SARS-CoV-2 reinfection adds risk of all-cause mortality, hospitalization and adverse health outcomes during acute and post-acute SARS-CoV-2 reinfection, and that the risk and burden may increase in a graded manner according to the number of infections, suggests preventing reinfection could reduce overall SARS-CoV-2 burden of death and disease in Ontario.

To minimize morbidity and mortality, as well as societal disruption, current public health responses could be augmented based on the epidemiological context, using interventions that reduce the risk SARS-CoV-2 transmission. Public health measures may include staying home when sick or with symptoms of COVID-19, ventilation, use of outdoor spaces and modes of transportation, and wearing a well-fitted mask whenever feasible when indoors in closed spaces, crowded places, and close contact settings (e.g., public transit).

SARS-CoV-2 Omicron Variant Sub-Lineages BA.4 and BA.5: Evidence and Risk Assessment

(up to date as of June 23, 2022)

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Issue and Research Question

There are multiple PANGO sub-lineages associated with the B.1.1.529 (Omicron) variant of concern (VOC). The main BA.1, BA.2, BA.3, BA.4, and BA.5 sub-lineages may also have their own sub-lineages (e.g., BA.1.1, BA.2.12, BA.2.12.1, BA.2.3, BA. 2.20, BA.2.9, BA.5.1). Considering the possible changes to transmissibility, severity, and/or vaccine effectiveness (VE) of these sub-lineages compared to other VOCs, it is important to monitor the potential impact they might have in Ontario's context. This evidence brief updates the Public Health Ontario (PHO) BA.4 and BA.5 report published on SARS-CoV-2 Omicron variant sub-lineages BA.4 and BA.5.

Methods

PHO Library Services conducted daily searches of primary and preprint literature using the MEDLINE database (search strategies available upon request). Preprints are research papers that have not undergone peer-review but are made publicly available to provide the latest data relevant to the rapidly evolving COVID-19 pandemic. Formal critical appraisal of published and preprint COVID-19 literature is out of scope for this PHO risk assessment. PHO performed grey literature searches daily using various news feeds and custom search engines. English-language peer-reviewed and preprint records that described COVID-19 variants were included. Sections from prior risk assessments for which there is no new literature of note are removed from the current update.

Ontario Risk Assessment

The current risk of BA.4 and BA.5 transmissibility in Ontario is high with a low degree of uncertainty. The risk of severe disease is low with a high degree of uncertainty. The risks of reinfection and of breakthrough infection are high with a moderate degree of uncertainty, given the evidence that BA.4 and BA.5 may evade neutralizing antibodies acquired by vaccination or generated from previous BA.1.1 infection, and to a lesser extent BA.2 infection. The risk of impact on testing is low with a moderate degree of uncertainty. The overall risk assessment may change as new evidence emerges (see Table 1).

Additional Considerations

Post-COVID-19 sequelae (PACS or "long-COVID") are not included in the risk assessment table, but several reviews report that the sequelae and their incidence vary.2-6 If considering PACS in a population or individual risk assessment, the risk could be moderate with a moderate degree of uncertainty. Preventing high levels of COVID-19 community transmission may mitigate the incidence of PACS and its long term impacts.

Emerging evidence indicates that reinfection adds risk of all-cause mortality, hospitalization and adverse health outcomes during acute and post-acute SARS-CoV-2 reinfection. Additionally, the risk and burden may increase in a graded manner according to the number of infections, which suggests preventing reinfection could reduce overall SARS-CoV-2 burden of death and disease.7 Current COVID-19 vaccines and previous SARS-CoV-2 infection do not provide sterilizing immunity (i.e., full protection from infection or reinfection).

Even if BA.4 or BA.5 are found to be no more severe than BA.1 and BA.2, the increased transmissibility potential of BA.4 and BA.5 suggests that the total number of cases (and potentially the total number of severe cases) would be expected to rise. High vaccine uptake, partial immunity from previous infections, and having additional public health measures in place may attenuate an increase in cases from BA.4 and BA.5, and their impact in Ontario.

SARS-CoV-2 Omicron Variant Sub-Lineages BA.4 and BA.5: Evidence and Risk Assessment

(up to date as of June 23, 2022)

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 The emergence of new Omicron sub-lineages in Ontario introduces uncertainty until more is known about their transmissibility, severity, immune evasion, and detection potential in the Ontario context.

Although South Africa's progress through its combined BA.4 and BA.5 wave is ahead of the rest of the world, the epidemic curve experienced in South Africa may not be generalizable to the Ontario context due to differences in history of previous SARS-CoV-2 infection, vaccination status, public health measures, as well as age distribution of the population.8 Portugal's recent experience with BA.5 is more applicable to the Ontario context but still has limitations.

COVID-19 hospitalizations have decreased after the decline of the BA.1 wave; however, health care worker absences, shortages, and impacts to scheduled care may remain challenging during this current period of prolonged community transmission. Transmission of other respiratory viruses (e.g., influenza) is another consideration for health care system recovery and capacity planning in Ontario.9

Although summers have been lower transmission periods for COVID-19 in Ontario during the past two years, and people can gather outdoors which lowers the risk of transmission events, key considerations for increased risk in Ontario at this time include (in no particular order): first, SARS-CoV-2 VE against infection has been waning in individuals last vaccinated more than four months ago, and more so in individuals who received two doses compared to three doses (based on studies from earlier Omicron waves); second, BA.4 and BA.5 are more transmissible than earlier sub-lineages and their proportional representation in Ontario is increasing according to WGS surveillance activities; third, although strains may share a common ancestor and sublineage, there can be significant point mutations and antigenic changes between evolving strains of the same sub-lineage (e.g., BA.2.12 versus BA.2.12.1, BA.2 versus BA.4/5), resulting in variable antibody cross-neutralization after an infection. As a result, reinfections and breakthrough infections may result in a resurgence of COVID-19.

Table 1. Risk Assessment for Omicron Sub-Lineages BA.5 and BA.4

Issues Increased Transmissibility Disease Severity COVID-19 Reinfection Lowered Vaccine Effectiveness or Breakthrough Infection Impact on Testing

Risk Level Degree of Uncertainty

High

Low

Low

High

High

Moderate

High

Moderate

Low

Moderate

SARS-CoV-2 Omicron Variant Sub-Lineages BA.4 and BA.5: Evidence and Risk Assessment

(up to date as of June 23, 2022)

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Genetic Features

BA.5 and BA.4 have the same spike (S) gene mutation profile, but have different sets of mutations in the rest of their genome.10

Signature mutations in the S protein of BA.4 and BA.5 compared to BA.2 include 69-70, L452R, F486V and R493Q.1.10,11

Additional mutations present in BA.4 but not in BA.5 include ORF1a:141/143, ORF6: D61L, ORF7b:L11F, and N:P151S.

A mutation present in BA.5 but not BA.4 is M:D3N.

A sub-lineage of BA.5, BA.5.1, has been described with an additional mutation ORF10:L37F.

Epidemiology

Globally

As of June 19, 2022, 11,376 BA.5 sequences have been reported in at least 59 countries, and 10,812 BA.4 sequences have been reported in at least 57 countries.12,13 BA.5 represents 24.78% of all Omicron lineages submitted to GISAID as of June 197, 2022, with an increase of 8.67% from the week ending June 12 to the week ending June 19, 2022.14 Meanwhile, BA.4 represents 8.62% of all Omicron lineages submitted to GISAID as of June 19, 2022, with an increase of 2.35% from the week ending June 12 to the week ending June 19, 2022.14 An increase in COVID19 cases, without concurrent increase in hospitalizations and intensive care unit (ICU) admissions, was seen in several WHO regions that reported an increase in BA.5 and BA.4 prevalence; however, hospitalization and ICU admission are lagging indicators.14

In South Africa, BA.5 was first detected in January 2022.15 BA.5 comprised 3% of all variants sequenced in March 2022. By April and May 2022, the proportion of BA.5 among all sequenced variants rose to 19% and 26%, respectively.16 BA.4 was first detected in February 2022.15 BA.4 comprised 13% of all variants sequenced in March 2022. By April and May 2022, the proportion of BA.4 among all sequenced variants rose to 54% and 68%, respectively.

BA.4 and BA.5 together became dominant (73%) in April, and comprised 94% of all sequenced samples in May.

From May 11, 2022, test positivity rates for COVID-19 have been declining from 25.3% to 4.1% on June 20, 2022,17 compared to a peak test positivity rate of 35.1% on December 21, 2021 during the BA.1 wave.1 Epidemiological trends suggest the BA.4 and BA.5 wave in South Africa has passed its peak.

The 7-day average test positivity on June 22, 2022 was 7.6%, which was lower than the day before (8.1%).17

Weekly incidence risk reported by all nine provinces have been declining by 45.2% for the week ending June 4, 2022,18 and by 35.1% for the week ending June 11, 2022.19

SARS-CoV-2 Omicron Variant Sub-Lineages BA.4 and BA.5: Evidence and Risk Assessment

(up to date as of June 23, 2022)

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 Weekly hospitalization risk has been declining by 41% for the week ending June 4, 2022,20 and by 33% for the week ending June 11, 2022.21

Portugal was the first European Union/European Economic Area (EU/EEA) country to report a significant increase in BA.5 case counts, and BA.5 comprised 88% of cases based on random sample sequencing in the week of June 6-12, 2022.22 The relative frequency of BA.2, BA.2.12.1, and BA.2.35 have been declining since BA.5 relative frequency began increasing. Portugal's most recent wave began the first week of June 2022. In recent weeks, case counts have stabilized and decreased, suggesting that the BA.5 peak was reached in the region.23 Meanwhile, the European Centre for Disease Prevention and Control epidemiological update on June 13, 2022 reported that BA.4 and BA.5 are expected to soon become the dominant sub-lineages in the EU/EEA, likely resulting in increasing cases in these regions.10

In the United States, the estimated proportions of BA.5 and BA.4 among circulating variants have been increasing, from ................
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