Safety and Immunogenicity of Mix-Match of Vaccines -Covishield and Covaxin – a Pilot Study

: This single-center prospective observational study was conducted to assess the safety and immunogenicity of combination vaccines AstraZeneca’s ChAdOx1 -nCov-19 (Covishield in India) and inactivated whole virion BBV152 (Covaxin). A total of 330 unvaccinated healthy volunteers were screened for SARS-COV2 seropositivity. RT PCR tests were conducted for seronegative volunteers (n =44). They were randomly assigned to four groups and given either same or mixed vaccines at an interval of 4 weeks between the two doses. Mix and match of vaccines did not evoke any adverse events. Combination of vaccines elicited similar immune responses in 4 groups. They were further studied dividing into homologous and heterologous vaccine groups. In Conclusion, Combination vaccines are safe and immunogenic and heterologous vaccines elicit better immunogenic response.


INTRODUCTION:
Vaccination has been shown to be protective against severe COVID-19 disease by various studies 1,2,3,4 . However, the vaccine efficacy was demonstrated to be less effective against the emerging variants of SARS-CoV-2 5 . Recent studies by Kant R et al., 6 Com-COV study 7 , Combi Vacs trial 8 , ChAdOx1 nCoV-19, and BNT162b2 9 have all demonstrated greater immunogenic response and increased protective efficacy with combination of vaccines. All these studies mainly focussed on Pfizer (BNT162b2), Moderna (mRNA-1273) and AstraZeneneca (ChAdOx1-nCov-19). We aimed to assess the safety and immunogenicity of combination of AstraZeneca's ChAdOx1-nCov-19 (Covishield in India) and inactivated whole virion BBV152 (Covaxin) with 4 weeks' interval. This study was conducted to reduce various difficulties in vaccinating populations across the world specially to mitigate vaccine deficit.

Materials and Methods:
This is a single-centre prospective observational study conducted at AIG Hospitals, Hyderabad, India. The study protocol was approved by the Institutional ethics committee (AIG/IEC-CT 51/08.2021-01). We recruited 330 healthy volunteers and screened for seronegativity for SARS-CoV-2 antibodies (IgM and IgG by chemiluminiscence; Roche Cobas e 601) and SARS-CoV2 negative report by RT-PCR. 3 ml of blood was drawn for screening SARS-COV2 antibodies. Nasopharyngeal swabs were collected from individuals who were seronegative (n=44) for SARS-CoV RT-PCR employing Taq path kits (Thermoscientific, USA). All the volunteers have provided written informed consent. Eligible participants (n=44) were divided randomly into four groups. (Figure 1). Group1-Covishield -Covishield group (homologous), Group 2 Covaxin -Covaxin group (homologous), Group 3 -Covishield -Covaxin group (heterologous), Group 4 -Covaxin -Covishield group (heterologous). Healthy volunteers were given 1st dose of Covishield (0.5 ml of intramuscular in deltoid) in group 1 and group 3 while volunteers in group 2 and group 4 received Covaxin (0.5 ml of intramuscular in deltoid) as 1st dose. After 4 weeks of 1 st dose, groups 1 and 4 received Covishield as 2 nd dose while groups 2 and 3 received Covaxin as 2 nd dose respectively. Further, the volunteers were divided into homologous (similar vaccines for two doses; group A) and heterologous (mix-match of vaccines for two doses; group B) vaccination groups and their antibody titers were evaluated to assess the immunogenic response. S1/S2 neutralizing antibodies titers and RBD specific antibody titers were evaluated at day 28 after the 1st dose and day 15 after the second dose (45 days of first dose) of vaccination; Sera were tested for S1/S2 antibody titers using chemiluminiscence assays (automated Diasorin Liaison XL, Italy) and electrochemiluminescent assays for RBD specific antibody titer (Cobas e 601,Roche Diagnostics, Basel, Switzerland).They were carefully monitored for any adverse events for 60 days. The data including demographics were entered in MS-excel and analyzed using SPSS version 23.
Categorical variables were expressed in percentages (frequency distribution) and continuous variables as mean and standard deviation (SD), median and range wherever required. Chisquare tests, student t-test and ANOVA were used appropriately.

Results:
A total of 44 participants out of 330 healthy volunteers were eligible for mix and match vaccine study (mix-vac study). Among 44 volunteers, 21 received the homologous vaccines and 23 received the heterologous vaccines. The mean age in Covishield homologous vaccine group was 34.83±7.58 years, and Covaxin homologous vaccine group was 31.33±5.20 years, Covishield followed by Covaxin heterologous group is 31.58±5.32 years and Covaxin followed by Covishield heterologous group was 32.27±5.26 years with no significant difference (p=0.49). There is no significant difference between the groups with respect to comorbidities like hypertension (Table-1 (Table-1). There are no major adverse events noted in the mix-match vaccine groups.  Figure 3; Figure   4).  Our study is the first Indian prospective pilot study demonstrating the safety and immunogenicity of mix-match vaccines with Covaxin and Covishield in healthy volunteers.
These results are similar to those conducted by Kant R et al(n=18) 6 which included only Covishield first dose followed by Covaxin, while our study included both Covishield followed by Covaxin and Covaxin followed by Covishield groups. The major limitation of the study was the smaller number (n=44). Despite the small number, our study included two groups with two combination of vaccines that are in use in this part of the world. However, these results need to be assessed in larger cohorts. Since the number is small in this study, our results do not interpret the best combination but it helps to answer the apprehensions among the general public about combination vaccine and prevent vaccine hesitancy.

Conclusion:
Our results show safety and immunogenicity of mix-match of COVID-19 vaccination (Covishield followed by Covaxin, and Covaxin followed by Covishield) and demonstrate enhanced antibody response with heterologous vaccines than homologous vaccines.