Inequitable vaccine availability adds to the problem as on one hand, in many high-income countries, a fourth dose of an mRNA vaccine is offered and gives well tolerated boosting of cellular and humoral immunity,1 and on the other hand, only 19·7% of people in low-income countries have received at least one dose of any COVID-19 vaccine.2 These facts all make it difficult to comment on what a primary COVID-19 vaccination series should consist of and how we should boost protective immunity in the face of emerging variants in a world with marked inequalities. ...the final analysis of the double-blind phase of the ENSEMBLE vaccine trial showed that primary vaccination with a single dose of Ad26.COV2.S had 56·3% (95% CI 51·3–60·8) efficacy against moderate to severe–critical COVID-19, 74·6% (64·7–82·1) efficacy against severe–critical COVID-19, and 82·8% (40·5–96·8) efficacy against COVID-19 related death.4 The data collection for the primary analyses of one-dose and two-dose regimens was completed before the global dominance of delta (B.1.617.2) and the emergence of omicron. ...we consider that two doses should be regarded as the primary vaccination series for Ad26.COV2.S in the era of omicron.