Immunogenicity and Safety of an Intradermal BNT162b2 mRNA Vaccine Booster after Two Doses of Inactivated SARS-CoV-2 Vaccine in Healthy Population

Abstract

Effective vaccine coverage is urgently needed to tackle the COVID-19 pandemic. Inactivated vaccines have been introduced in many countries for emergency usage, but have only provided limited protection. Heterologous vaccination is a promising strategy to maximise vaccine immunogenicity. Here, we conducted a phase I, randomised control trial to observe the safety and immunogenicity after an intradermal boost, using a fractional dosage (1:5) of BNT162b2 mRNA vaccine in healthy participants in Songkhla, Thailand. In total, 91 volunteers who had been administered with two doses of inactivated SARS-CoV-2 (CoronaVac) were recruited into the study, and then randomised (1:1:1) to received different regimens of the third dose. An intramuscular booster with a full dose of BNT162b2 was included as a conventional control, and a half dose group was included as reciprocal comparator. Both, immediate and delayed adverse events following immunisation (AEFI) were monitored. Humoral and cellular immune responses were examined to observe the booster effects. The intradermal booster provided significantly fewer systemic side effects, from 70% down to 19.4% (p < 0.001); however, they were comparable to local reactions with the conventional intramuscular booster. In the intradermal group after receiving only one fifth of the conventional dosage, serum Anti-RBD IgG was halved compared to the full dose of an intramuscular injection. However, the neutralising function against the Delta strain remained intact. T cell responses were also less effective in the intradermal group compared to the intramuscular booster. Together, the intradermal booster, using a fractional dose of BNT162b2, can reduce systemic reactions and provides a good level and function of antibody responses compared to the conventional booster. This favourable intradermal boosting strategy provides a suitable alternative for vaccines and effective vaccine management to increase the coverage during the vaccine shortage.

Keywords: COVID-19; immunogenicity; inactivated SARS-CoV-2; intradermal; mRNA vaccine.

Figure 1

CONSORT chart. Abbreviations: intradermal (ID); intramuscular (IM).

Figure 2

Solicited local adverse reactions at 30 min and 7 days after boosting. Full dose (blue) and half dose (orange) of intramuscular mRNA booster, after completed vaccination with two doses of inactivated SARS-CoV-2. Some of the previously vaccinated individuals were boosted with a fractional dose of intradermal mRNA vaccine (yellow). (A) The immediate and delayed local reactions were observed after injection. (B) Seven days after boosting, local adverse events were recorded for comparing between booster groups.

Figure 3

Solicited systemic adverse reactions at 7 days after boosting. Full dose and half dose of the mRNA vaccine were given intramuscularly after two doses of inactivated SARS-CoV-2 vaccines (PZ IM, full dose and half dose). One-fifth of the standard mRNA vaccine dose was delivered intradermally (PZ ID, 1:5 dose). (A) The systemic adverse events were graded, as per medical needs, and presented in percentage. The self-limited systemic reactions were grade 1 (green). The reactions requiring medications were grade 2 (orange), in need of medical attention were grade 3 (red). (B) Systemic reactions were presented separately to compare between the three vaccinated groups.

Figure 4

Antibody responses and neutralising function after boosting. Participants who had received two doses of inactivated SARS-CoV-2 vaccines were recruited in this study (SV SV). Conventional (full dose) and fractional dose (half dose) of the mRNA vaccine were administered intramuscularly (SV SV PZ IM). The fractional dose (1:5 dose) of the mRNA boost was delivered intradermally (SV SV PZ ID). Blood was collected pre (D0) and post boosting 14, 28 days (D14, D28). (A) Serum samples were analysed using CMIA to measure anti-RBD IgG. (B) Neutralising antibodies against the Delta variant was tested using PRNT. Convalescent sera were included as controls. Each symbol represents one participant, and the number is the median of each group (n = 30–31 volunteers). Statistical significance was determined using the Kruskal–Wallis test, with Dunn’s multiple comparisons test. *** p ≤ 0.001; **** p ≤ 0.0001.

Figure 5

T cell responses after boosting. All volunteers were previously vaccinated with two doses of inactivated SARS-CoV-2 vaccines (SV SV). The fractional dose (1/5 dose) of the mRNA vaccine was injected intradermally, as a booster dose (SV SV PZ ID). Full doses and half doses of the mRNA vaccine were immunised intramuscularly as a standard route of injection (SV SV PZ IM). Blood was drawn before (D0) and after the booster dose for 14 days (D14). The blood samples were processed to obtain PBMCs. The fresh PBMCs were stimulated with S1 peptide pools, before measuring IFN-γ secreted cells, using ELISpot. Each symbol represents one participant, and the number is the median of each group (n = 30–31 volunteers). Statistical significance was determined using the Kruskal–Wallis test, with Dunn’s multiple comparisons test. *, p ≤ 0.05; ns = non significance.