Discussion
infection, SARS-CoV-2 infection, infections, acute SARS-CoV-2 infection
VIRUS, SARS-COV-2 INFECTION, ASYMPTOMATIC SARS-COV-2 INFECTION, INFECTIONS, INFECTION
The main findings of this study are that the vaccine candidate ARVAC CG when given as a booster dose is well tolerated and induces a robust and broad nAb response against several SARS-CoV-2 VOCs.The interim results of this phase 1 study indicate that ARVAC CG vaccine given to individuals who previously received a complete primary vaccination regimen has a clinically acceptable safety and reactogenicity profile for both antigen doses (25 μg and 50 μg).Immunogenicity results indicate that ARVAC CG as a booster dose induces a sharp increase of broadly nAb titres against the Ancestral SARS-CoV-2 strain, the Gamma SARS-CoV-2 VOC, which is the vaccine prototype strain, as well as against antigenic distant SARS-CoV-2 VOCs like Delta, Omicron BA.1 and Omicron BA.5. Moreover, the ARVAC CG 50 μg dose outperformed the 25 μg dose in terms of nAb titers reached against the Ancestral and Omicron BA.1 viral variants and 10×-seroconversion rates in nAb against Omicron BA.1. The booster effect after one dose of ARVAC CG vaccine was evident despite the variety of immunization schemes received by the study participants.The differences in the proportions of subjects with different types of primary vaccine regimen in the low-dose and the high-dose groups may difficult comparisons. However, the possibility to include different primary vaccination schemes was important in this phase 1 study to have a representation of the diversity in primary vaccination schemes that were used in Argentina. Since most individuals in group B had received the BBIBP-CorV vaccine as primary vaccination regimen and there were approximately equal numbers of BBIBP-CorV recipients in the high and low dose groups, the comparison of these subgroups was also performed. Similar to the findings when all volunteers were included, in these more homogeneous subpopulations, the 50 µg dose was consistently more immunogenic than the 25 µg dose. Although the time since prior COVID-19 declared by participants was quite different between the high and low dose groups and this could be a limitation, the analysis of anti-N in sera of all individuals indicated that both populations were similar in their inferred previous exposure to the virus and that the immune responses after vaccination are independent of previous infection status.With the emergence of new VOCs it is clear that breakthrough infections can occur in vaccinated persons, including those with previous SARS-CoV-2 infectionThe performance of the ARVAC CG booster dose regarding nAb GMTs and GMFR, was similar to that of the BNT162b2 booster against Ancestral and Delta VOCs, but better for Gamma, Omicron BA.1 and BA.5 VOCs. Similarly, booster shots with Beta variant-based vaccines elicit broad nAb responses against the Ancestral, the Beta and the Omicron BA.1 VOC, which were higher than that elicited by a booster with an ancestral-variant based vaccineEven though there are not well-established threshold values of nAb levels that correlate with protection against symptomatic SARS-CoV-2 infection, an increasing number of studies using standardized methods offer hints about the nAb levels that might be associated with protectionT-cell immunity is crucial to combat acute SARS-CoV-2 infection and for the development of long-term immunityOne limitation of this study is the lack of randomization for volunteers. Nevertheless, despite the sequential study design, enrolment dates of the booster groups occurred within weeks of each other, representing similar epidemiologic environments of circulating variants. The comparison of the immunogenicity results of ARVAC CG cohorts with those of a contemporaneous BNT162b2 booster study has another limitation, since the study participants presented some demographic differences in their ages (36.5 in BNT162b2 group versus 32 and 27 years in groups A and B, respectively). Although the time from last SARS-CoV-2 vaccine dose (4.2 months in the BNT162b2 boosted subjects versus 7.9 and 6.6 months in group A and B, respectively) was different this did not influence the immune outcomes in this study. Peak of nAb titers reached after booster in both ARVAC CG cohorts were similar whether the time since primary vaccination completion to booster was short ( < 180 days) or long (≥ 180 days). Indeed, ARVAC CG boosters at short time ( < 180 days) showed a better performance than BNT162b2 booster. The confirmed previous SARS-CoV-2 infection history (0% in group BNT162b2 versus 8% and 20% in groups A and B, respectively) was quite different, nevertheless anti-N antibodies serology indicated that the three populations had similar proportions of seropositive individuals and might had similar previous contact with the virus. The proportion of primary vaccination schemes was also different, since most individuals in BNT162b2 boosted cohort had received the rAd26/rAd5 (Sputnik V) vaccine as primary vaccination regimen, however the comparison among subjects with the same primary vaccination led to similar results.In this phase 1 study, safety was demonstrated after two ARVAC CG administrations highlighting that ARVAC CG is safe. Immune responses after a single booster dose could be assessed only after 14 and 28 days of administration. After the second ARVAC CG administration the nAb remained significantly higher than baseline but no booster effect was observed. The lack of booster effect may be due to the short interval between boosters, that may not be the optimal in terms of immunological performanceWhile both formulations of ARVAC CG exhibited a favorable safety and reactogenicity profile eliciting broadly nAb responses and T cell immunity against SARS-CoV-2, the 50 µg dose outperformed the 25 µg dose in certain of the immunogenicity variables evaluated. Therefore, the 50 µg dose vaccine is currently being tested in an ongoing Phase 2/3 study to evaluate its safety, and immunogenicity in a larger population. Selection of the 50 µg vaccine dose allowed the testing of a bivalent vaccine containing 25 µg of Gamma-based antigen plus 25 µg of Omicron BA.5-based antigen to improve the response capacity, as part of a Phase 2/3 study, in accordance with the recommendations from the advisory committee on immunization practices for the use of bivalent booster doses of COVID-19 vaccines to increase protection against circulating VOCs and to broaden neutralization to previous and potentially yet-to-emerge variantsThere is a need for widespread immunization programs with new generation of COVID-19 booster vaccines which provide a wide breadth of protection against constantly emerging SARS-Cov-2 variants. Nonetheless, LMICs lag far behind in this effort due to limitations in affordability and accessibility to vaccines. Hence, developments such as ARVAC CG may offer an opportunity to overcome some of these challenges and improve the response capacity of many countries, worldwide.