With XBB, XBC, and Scrabble variants now out, is the pandemic ever going to be over?

CLINICAL MATTERS

On Oct. 18, the Department of Health announced the detection of 81 cases of the recombinant XBB and 193 cases of the recombinant XBC. In the US and Europe, several new lineages colloquially referred to as “Scrabble” variants look like they may have immune escaping properties that could drive new spikes in cases. What do all these new variants mean as we strive to get to endemicity? Will we need to introduce new restrictions, keep old ones, or get updated vaccines? Will we have a good Christmas?

The good news is that all the original Covid-19 vaccines are continuing to protect against severe disease. These old monovalent (containing the old ancestral strain of SARS-CoV-2) vaccines, however, currently offer little protection against acquiring infection from the new variants. The continued mutation of the spike protein has decreased the neutralization abilities of antibodies generated by the ancestral viruses, resulting in significant immune escape. Recent estimates of the vaccine efficacy of Pfizer against different Omicron lineages show a very low efficacy when it comes to preventing symptomatic infection. Efficacy of protection against hospitalization from Omicron without a booster is about 65 percent, while the first booster increases this to 81 percent. A second monovalent booster seems to offer additional protection in those 60 years and above, but there is no convincing data a second booster helps in younger people. 

While there is continued hype that the upcoming variants are the “worst ever,” the truth is that all the Omicron sublineages have achieved a high level of immune evasion against infection and this is nothing new. Almost none of the monoclonal antibodies developed against the original SARS-CoV-2 virus have any effect on preventing infection with Omicron. Despite this, all the current vaccines still prevent severe disease at a very high rate. Restoring protection against infection is the main reason bivalent vaccines containing the original SARS-CoV-2 lineage, plus a second updated lineage were developed (see last week’s column https://mb.com.ph/2022/10/18/the-shot-that-saves-lives/), especially in the light of relaxation of mask mandates. The first bivalent vaccine formulation was approved in the UK and consists of a mixture of the original ancestral lineage plus Omicron BA.1. The subsequent bivalent vaccine approvals in the US and Canada were delayed because regulators wanted a bivalent vaccine based on BA.4/BA.5 in order to maximize antibody neutralization potential. This is what is being given currently in these countries and it is hoped it will head off a potential surge in cases this winter season as people spend more time indoors.

As more lineages and recombinants are discovered, classification schemes are modified and some previous lineages are renamed, reclassified, or combined. The original lineage naming convention originated by Pangolin system (Phylogenetic Assignment of Named Global Outbreak LINeages) consists of a letter only for an original lineage with subsequent descendant lineages designated by one or more numbers. For example, there are two original Wuhan lineages designated A and B. Subsequent lineages are designated A.1, B.1, A.2, B.2 and so on. Sublineages of B.1 are designated B.1.1, B.1.2, B.1.3 and so on. Sublineages of B.1.1 are named B.1.1.1, B.1.1.2, B.1.1.3 and so on.

When the number of sublineages reaches four generations, a new letter is assigned with one number. For instance, the variant of interest Theta that emerged in the Philippines is also known as sublineage B.1.1.28.3 and was subsequently designated P.3. After the letter Z is reached, two letters were assigned: AA.1, BA.1, BX.1. The designation of a lineage itself is somewhat arbitrary as not every single mutation merits a new lineage. New proposed lineages need to be geographically distinct and contain enough new mutations in significant regions to merit a new sublineage designation. 

Variants of concern (VOC) as designated by the World Health Organization are part of a separate classification system. VOCs are lineages and sublineages, which fulfill specific criteria, including an increase in transmissibility or detrimental change in Covid-19 epidemiology, or an increase in virulence or change in clinical disease presentation, or a decrease in effectiveness of public health and social measures or available diagnostics, vaccines, therapeutics. In general, VOCs also include subsequent lineages and recombinants of the VOC, unless a specific sublineage is designated as a new VOC. For instance, the Omicron VOC classification includes the original lineage B.1.1.251, plus subsequent sublineages BA.1, BA.2, BA.2.75 and the recombinants XE, XBB, and so on.

Recombinants occur when two viruses infect a person and the virus’ RNA is mixed in a certain way which then gets transmitted onward. When a recombinant is first discovered, it may be assigned to one of the parent lineages since that’s what fits in the classification algorithm. Closer examination reveals a combination of two viruses. This happened with XBC, which was originally classified as a Delta subvariant but ended up being an Omicron and Delta recombinant. On reanalysis of recent cases from Mindanao, which were initially classified as Delta, these turned out to be XBC under the newest classification system updates, hence the large initial number of cases.

XBB, a recombinant form of two Omicron lineages BA.2.75 and BA.2.10.1, is thought to be behind the recent spike of cases in Singapore. Fortunately, severe cases have remained low, underlying the continuing protection of our Covid-19 vaccines against even the newest variants. The difference in transmission potential can be a function of viral evolution. For instance, the D614G spike protein mutation boosted the infectivity of B.1 and subsequent lineages above and beyond that of many other lineages in June 2020, on its way to becoming the dominant variant. Current estimates of growth advantages of new lineages, however, are influenced by the continued relaxation of public health standards, particularly the removal of mask mandates. While there is clear laboratory data to support the increased infectivity of D614G using viral constructs, many of the current estimates of transmissibility for newer lineages and sublineages are based on growth curve models, which are affected by many, many variables, including continued adherence to public health standards.

This is reflected by the fact that XBB may have been circulating earlier in the Philippines as shown by the high number of initial transmissions detected. There have been no significant spikes in cases, however, nor an increase in the number of hospital admissions. Many people are now just testing with antigen tests and not proceeding to RT-PCR, unless they end up hospitalized or need to document their illness for insurance purposes. Therefore, the actual number of cases being reported is an underestimate of the cases in the community. In fact, this makes positivity rate unreliable as any kind of meaningful measure of disease activity because RT-PCR tests will be biased toward those who already are antigen positive or are ill enough to end up in the hospital. Despite this underestimate in cases, however, we know that most hospitalized and severe cases will still undergo RT-PCR testing so these will be reported. Healthcare utilization capacity remains low whatever the true number of cases. This is the ultimate determining factor on whether we continue to monitor only or we need to tighten up restrictions anew. Hospital utilization of Covid-19 beds remains below 30 percent at this time and so no new restrictions are needed.

Moving forward, what is the most prudent course of action? As we continue to investigate XBC and track the spread of XBB, it may be wise to pause further relaxation of mask mandates while we await the arrival of the new bivalent vaccines. The current vaccines are expected to continue protecting against severe disease for both XBB and XBC, but bivalent vaccines may help reduce transmissibility. In the meantime, masks will continue to work to decrease the probability of a large spike in cases and we should continue using these for now. Barring any sudden spikes in cases, which increase healthcare utilization beyond 50 percent, additional restrictions or a rollback to stricter mandates are unnecessary. A good Christmas is definitely doable, and we hope the bivalent vaccines get here soon as an additional insurance measure. 

In the meantime, the march toward endemicity continues. It may come in fits and starts, but as long as it is headed in the right direction, we will be okay.