COVID-19 variants not neutralised by Evusheld

14th October 2022

Not all of the recently identified COVID-19 variants can be neutralised by Evusheld according to an updated factsheet issued by the FDA

Exposure to some recently identified COVID-19 variants pose an increased risk for developing COVID-19 according to the US food and drug administration (FDA). The release warns that health care professionals should inform patients of this risk and advise patients who develop signs or symptoms of COVID-19 to get tested and promptly seek medical attention, including starting treatment for COVID-19, as appropriate if they test positive.

Evusheld consists of a 300mg dose of both tixagevimab and cilgavimab that are administered as two separate, sequential IM injections. According to its summary of product characteristics, the combination is indicated for the pre-exposure prophylaxis of COVID-19 in adults who are not currently infected with the virus and who have not had a known recent exposure to a COVID-19 infected individual infected and who are unlikely to mount an adequate immune response to a COVID-19 vaccination or where vaccination is not recommended. Data from the TACKLE study showed that a single intramuscular tixagevimab-cilgavimab dose provided statistically and clinically significant protection against progression to severe COVID-19 or death compared to placebo in unvaccinated individuals.

Over time as the COVID-19 virus has mutated, several COVID-19 variants have emerged in particular, the omicron variant which has been divided into five distinct sub-lineages: BA.1, BA.2, BA.3, BA.4, and BA.5. A major concern has therefore been whether existing therapies are still capable of neutralising these emerging variants. Thankfully, studies in mice has shown that Evusheld (AZD7442) retains neutralising activity against the Omicron lineage strains BA.1, BA.1.1 and BA.2. However, as more variants emerge, the latest FDA update suggests that certain COVID-19 variants may not be neutralised by monoclonal antibodies such as tixagevimab and cilgavimab (i.e., Evusheld).

COVID-19 variants and Evusheld neutralisation

The update includes in vitro neutralisation data showing that there is a greater than 1000-fold reduction in susceptibility for the COVID-19 variant BA.4.6 with Evusheld and data from the CDC in the US currently shows that BA4.6 represents 12.8% of the circulating variants of concern.

The FDA also adds that ‘the use of Evusheld is not a substitute for COVID-19 vaccination and individuals for whom COVID-19 vaccination is recommended should get vaccinated.’ Despite this the FDA continues to recommend Evusheld as an appropriate option for pre-exposure prophylaxis to prevent COVID-19, in combination with other preventative measures like getting vaccinated and boosted as recommended. This is because Evusheld still offers protection against many of the currently circulating variants and may offer protection against future variants. 

Resistance mutations develop in Omicron sub-variant patients treated with sotrovimab

5th August 2022

Resistance mutations in the Omicron sub-variants quickly develop in patients treated with sotrovimab, thereby delaying the time to viral clearance

Resistance mutations have been found to develop after a few days treatment with sotrovimab in patients infected with Omicron sub-variants and which significantly delays the time to viral clearance. This was the conclusion of a small study by researchers from the University of Amsterdam.

Sotrovimab is an human monoclonal antibody that targets a highly conserved epitope in the COVID-19 spike protein at a region that does not compete with binding of the angiotensin-converting enzyme 2. The monoclonal antibody has been approved by the EMA to treat confirmed COVID-19 in adults and adolescents who do not require supplemental oxygen therapy and who are at risk of progressing to severe COVID-19.

However, there is a concern over the development of resistance mutations in monoclonal antibodies and this has already been observed with sotrovimab in patients infected with the delta variant. Sotrovimab is one of the few monoclonal antibodies that retains efficacy against the widely circulating Omicron BA.1 sub-lineage although whether resistance mutations can still develop in those infected with the omicron variant and its sub-variants is unclear.

In the present study, the Dutch team examined whether resistance mutations could develop during therapy with sotrovimab in patients infected with Omicron. A single 500mg dose of the drug was administered to a group of ambulatory, hospitalised, high-risk patients with COVID-19 and nasopharyngeal specimens were collected on days 0, 7 and 28 and subjected to whole-genome sequencing.

For the primary outcome, the Dutch team set the emergence of spike protein resistance-associated mutations at positions E340 or P337 during treatment with sotrovimab as the primary outcome. The team used a Cox proportional hazard model to estimate the time to viral clearance with resistance mutations as a covariate.

Resistance mutations and outcomes

A total of 47 high-risk patients were studied but only 18 had more than one nasopharyngeal specimen taken and included in the final analysis. The remaining patients either declined or could not be contacted.

For the final cohort, the mean age was 60.9 years (50% female) and 15 were immunocompromised due to either immunosuppressive conditions or treatments. All of the patients were given sotrovimab between 0 and 23 days after a positive PCR test for COVID-19.

Genomic analysis revealed that all patients were infected with the omicron variant, 17 with BA.1 and the remaining patient BA.2. Overall, 10 patients (56%) developed resistance mutations at spike position E340 or P337 within 3 to 31 days after treatment. Four patients developed resistance mutations to E340, all of whom were immunocompromised.

Furthermore, mutations developed quickly with more than 50% having arisen between days 5 and 28. In comparison to those without mutations, the time to viral clearance was significantly longer (32 vs 19.6 days), giving a hazard ratio of 0.11 (95% CI 0.02 – 0.60) in patients displaying resistance mutations.

While accepting the study was based on a small number of patients and that they did to include clinical outcomes for resistant patients, the authors called for further studies to investigate the value of combination monoclonal antibody therapy combined with genomic sequencing for immunocompromised patients.

Citation
Birnie E et al. Development of Resistance-Associated Mutations After Sotrovimab Administration in High-risk Individuals Infected With the SARS-CoV-2 Omicron Variant JAMA 2022

Bivalent Moderna vaccine likely to protect against Omicron sub-variants

26th June 2022

A bivalent Moderna vaccine was found to produce a potent neutralising antibody response against two Omicron sub-variants BA.4 and BA.5

A bivalent Moderna vaccine is able to generate a large neutralising antibody response against two of the Omicron sub-variants, BA.4 and BA.5 and therefore likely to protect against these variants.

Both the BA.4 and BA.5 sub-variants of Omicron were detected in South Africa in January and February 2022, respectively. Moreover, there have recently been concerns raised over these two sub-variants especially after a study published in the New England Journal of Medicine, found that the sub-variants, substantially escaped neutralising antibodies induced by both vaccination and infection.

The results of the study showed that among individuals who had received a third (i.e., booster) dose of BNT162b, compared with the response against the original COVID-19 isolate, the neutralising antibody titre was lower by a factor of 21 against BA.4 or BA.5. In other words, it appears highly likely that even among those who have been fully vaccinated, the BA.4 and BA.5 can lead to re-infection.

The bivalent Moderna vaccine has been studied in a phase 2 and phase 3 trial which has yet to be published. In the study, all participants who had previously received 2 or 3 doses of an approved COVID-19 vaccine were then given mRNA-1273.529, mRNA-1273.214, or mRNA-1273 as the 4th dose.

Bivalent Moderna vaccine and Omicron sub-variants

When considering the COVID booster candidate, mRNA-1273.214, only one month after administration in previously boosted participants, a 50 µg booster dose elicited potent neutralising antibody responses against the Omicron sub-variants BA.4 and BA.5 in all participants.

In fact, mRNA-1273.214 was able to increase the level of neutralising antibody titres against BA.4/BA.5 by 5.4-fold (95% CI 5.0 – 5.9) above baseline in all participants regardless of prior infection and by 6.3-fold (95% CI 5.7 – 6.9) in the subset of seronegative participants.

These results follow on from previous data from early June 2022, in which Moderna found that a booster dose with mRNA-1273.214 increased neutralising geometric mean titres (GMT) against the Omicron variant by approximately 8-fold above baseline levels.

Moreover, a 50 μg booster dose of mRNA-1273.214 was well-tolerated in the 437 study participants and both the safety and reactogenicity profile of mRNA-1273.214 was similar to that of mRNA-1273 when these vaccines were administered as a second booster dose.

Based on these preliminary findings, Moderna is now working hard to complete all the necessary regulatory submissions in the coming weeks requesting to update the composition of the booster vaccine to mRNA-1273.214.