New studies published on Research Square take an intensive look at Pfizer vaccine primary and booster regimens, with new models suggesting long-range transmission of SARS-CoV-2 and exploring the prevalence and symptom trajectory of long COVID.
From day 3 onwards, stable antibody levels to the spike protein were maintained, or at most a slight increase.
The sera of these patients also showed no detectable neutralization activity on day 0, except for those who had received Ronapreve earlier. After Evusheld was given, neutralizing activity against the Delta variant increased steeply, to ~800-1,000 BAU/mL, while no increase was seen with those who had received Ronapreve already.
Ronapreve administration was not associated with BA.1 neutralization, but with Evusheld, 7/8 individuals acquired neutralizing ability against BA.1 over the period from day 3 to day 30. Nonetheless, the neutralizing titers were extremely low, not exceeding 130 BAU/mL at day 15, and some as low as 27 BAU/mL. An increase in neutralizing titers did occur from day 3 to day 15.
The mAbs appear to act poorly against BA.1 as indicated by the delayed neutralizing activity, at low levels, on day 3. No BA.2 neutralization was observed at day 0 in Ronapreve-naïve patients, and a low level of BA.2 neutralizing activity was seen after Ronapreve administration. This supports the earlier findings that Indevimab can neutralize the latter strain.
Evusheld administration was associated with an increase in BA.2 administration, with the 50% effective dose (ED50) going up to 3,500 on day 15. In most patients, neutralizing activity was maintained at stable levels, indicating that Evusheld has a long half-life.
Anti-spike IgG levels and anti-Delta neutralizing activity showed strong correlations, but not with anti-BA.1 or anti-BA.2 neutralization, indicating that Omicron has strong immune evasion capabilities.
What Are the Implications?
The results show that therapeutic mAbs vary significantly in their ability to confer neutralizing immunity against Delta vs Omicron, as well as Omicron BA.1 vs BA.2. In addition, untreated immunocompromised individuals reacted poorly to the vaccine, neutralizing neither Delta or either Omicron strain.
With Ronapreve, Delta was neutralized, but not BA.1, while neutralizing titers were low against BA.2. Evusheld led to detectable neutralizing activity against BA.1 in individuals who had not received Ronapreve, and 100% BA.2 neutralization, indicating that this cocktail neutralizes BA.2 better than BA.1.
The ED50 against Delta was >15,000 after Evusheld, and >70,000 after Ronapreve/Evusheld, but <50 against BA.1. Against BA.2, ED50 was above 1,500, indicating efficient neutralization even though the titers were reduced almost 10- and 40-fold compared to Delta neutralization. That is, neutralizing titers were comparable irrespective of whether both or only one mAb cocktail was administered.
In order to protect against infection before exposure to the virus, the mAbs used must be active against the circulating variants. In the current situation, where BA.1 and BA.2 are co-circulating, mAbs like Bebtelovimab must be preferred, with activity against both strains.
Secondly, serologic tests that measure antibody binding and neutralization using the wildtype spike are misleading as they do not indicate protection against current strains.
As of now, treatment failures may be expected to become more frequent with the use of currently available mAbs, while the accumulation of more mutations will lead to the emergence of still more antibody-resistant strains. The use of either Ronapreve or Evusheld may be fraught with the risk of promoting the emergence of such escape mutations due to their low to intermediate neutralizing activity.
