The virus causing COVID-19, SARS-CoV-2, continues to evolve with new mutations. With these RNA-viruses, frequent mutations and new variants are predictable because their accuracy of replication is lower than other virus types. These new variants are reducing the accuracy of some COVID-19 tests. Fortunately for Rako Science, our highly sensitive PCR saliva test has lost none of its accuracy with Delta and Omicron variants.
The new Omicron variant has more than 30 mutations in the spike protein upon which most COVID-19 vaccines target. Vaccine protection from infection following two doses may be as low as 10% for Omicron. Health officials in the US and Europe are now describing Omicron breakthrough infections in vaccinated people as routine. Governments have responded by accelerating their booster vaccination schedules to regain population protection. In New Zealand, if we consider a booster necessary to indicate “fully vaccinated”, then the proportion of the eligible population fully vaccinated takes us back to mid-2021 in terms of population protection.
The impact observed overseas reflects Omicron variant’s higher infectivity. The “R0 value” of a virus represents how many will be infected by a case. R0 has increased as the virus has evolved from 2.5 originally to approaching 7 for Delta to almost 10, or even higher, for Omicron. The incubation periods for new variants have also changed, becoming shorter, from 5-6 days to 4 days to 2-3 days respectively. In several countries cases have doubled in only 2-3 days. This poses a significant challenge for contact tracing because there is little time to react to a positive case to interrupt the chain of transmission. This increases the need for other measures to support public health interventions and high frequency testing is one of the more important tools to assist controlling spread.
The virus’s evolution has implications for testing for the virus. In the USA the Food and Drug Administration (FDA) and the National Institutes of Health (NIH) are constantly evaluating the impact of new mutations on different test methods. For PCR tests that target several gene targets, like Rako Science’s assay, performance is not expected to be negatively impacted. Our assay targets three genes; the spike gene (S), nucleocapsid (N), and a replication gene (ORF1ab). We require at least two genes to be detected to report a positive. Because of the S gene mutations present in Omicron the S gene is not detected in some Omicron variants. This is called “S-gene target failure (SGTF)” and is a strong indication that the infection is due to Omicron BA.1 lineage, as compared to the Delta variant. We are on alert for this pattern of test result but have yet to encounter one.
The FDA and NIH have reported that rapid antigen tests (RATs) detect the Omicron variant, but they may have reduced sensitivity. Tests with heat inactivated samples observed similar performance of RATs to detecting earlier variants. The FDA noted however that these laboratory-based data were not a replacement for clinical studies using patient samples with live virus, ie. real-life experience.
Last week preliminary real-life data was reported by a group with previous COVID-19 testing experience. In this study, staff in occupational safety programs were tested daily with a PCR saliva test and a nasal RAT test. Of relevance for New Zealand those being tested were all fully vaccinated by employer mandate and highly boosted by choice. Thirty cases with 62 matched pairs with RAT results and positive PCR results were analyzed. All individuals became symptomatic within two days of the first positive PCR saliva result. S-gene drop out was present in 29 of the 30 cases, i.e.. Omicron infections. On days 0 and 1 all RATs were falsely negative despite 28 of the 30 pairs having infectious viral loads. The median time from the first positive PCR to the first positive RAT was 3 days. Moreover, four cases were confirmed to have transmitted the virus between false-negative RAT results.
Previous studies have suggested that RATs have good sensitivity with high viral loads regarded as infectious as well as early in symptomatic infection. RATs were considered good at answering the question “Is this person infectious now?” The accepted lower sensitivity for detecting incubating infection could be addressed by frequent testing. How do we reconcile these differing observations? The most likely explanation rests on the setting, ie. Omicron infections in a vaccinated and boosted population. This is the situation we are heading for in New Zealand.
The implications for testing are significant. Here are some obvious conclusions:
High frequency testing that detects positive cases early is required to protect vulnerable people in places such as rest homes as well as essential workers, such as the health workforce, New Zealand Police, power generation and transportation.
If the test is not effective at early detection, then it cannot stop spread and provide that protection.
Rapid antigen tests are ineffective at detecting Omicron variant for the three days after a PCR saliva test detects the virus and this, combined with the earlier onset of infectiousness, means their use will not help stopping spread or protect vulnerable people or essential workers.
Rapid antigen tests can be used in lower risk settings at home or settings where a rapid result can assist with decision-making. But strong and clear messaging is necessary to ensure false negatives do not give people false confidence that leads to increased spread.
Dr Arthur Morris.
Arthur Morris is a pathologist, clinical microbiologist, with a long-term interest in infection prevention and control. He is the supervising pathologist for IGENZ.
In January 2021, IGENZ Ltd, a contracted testing laboratory, achieved IANZ accreditation for saliva testing using the Rako Science methodology, based on validation work that used a set of contemporaneously collected paired saliva and nasopharyngeal samples.
 Discordant SARS-CoV-2 PCR and Rapid Antigen Test Results When Infectious: A December 2021 Occupational Case Series (medrxiv.org)