The Relationship Between the Immunogenicity and Reactogenicity of a Seasonal Influenza Vaccine Delivered by Microneedle Patch or Hypodermic Needle Öffentlichkeit

Gromer, Daniel (Spring 2024)

Permanent URL: https://etd.library.emory.edu/concern/etds/j3860843v?locale=de
Published

Abstract

Background: Vaccine immunogenicity and reactogenicity each depend on recipient and vaccine characteristics. An association between these two vaccine outcomes would have major implications for clinical care, public health, and vaccine development. We hypothesized that healthy adults who reported higher reactogenicity from seasonal inactivated influenza vaccine (IIV) developed higher antibody titers compared with those who reported lower reactogenicity.

Methods: We performed a secondary analysis of the TIV-MNP 2015 study, a randomized phase 1 clinical trial comparing the immunogenicity and reactogenicity of a trivalent IIV delivered by microneedle patch (MNP) or intramuscular injection (IM). We created composite scores of solicited adverse events (Global, Systemic, and Local) as the exposure and hemagglutination inhibition (HAI) antibody titers against the H1N1, H3N2, and B antigens in the vaccine as the outcome. To account for longitudinal outcome data, we used mixed model analysis of variance to estimate geometric mean titers (GMTs), GMT ratios (GMRs), and titer fold change ratios (FCRs) and modified Poisson generalized estimating equations to estimate risk ratios (RRs) of HAI seroprotection and seroconversion. We adjusted for several confounders and generated estimates separately by vaccine delivery method.

Results: The IM (n=25) and MNP (n=50) groups were balanced in baseline characteristics. Longitudinal estimates of H3N2 HAI GMTs were associated with the Systemic and Local scores among the IM group. Within the IM group, those with high reaction scores had lower baseline H3N2 HAI GMTs (Global GMR 0.5, p=0.06; Systemic GMR 0.4, p=0.01; Local GMR 0.3, p=0.01) and twice the titer fold change by day 28 (Global FCR 2.0, p=0.04; Systemic FCR 1.9, p=0.07; Local FCR 2.0, p=0.15) compared with those with low reaction scores. Those with high Local scores had a higher risk of HAI seroconversion (RR 1.4, p=0.03).

Conclusion: These results suggest that heightened reactogenicity to intramuscular inactivated influenza vaccine is related to low baseline humoral immunity to an included antigen. Participants with greater reactogenicity developed greater antibody titer fold change after 4 weeks, though the overall magnitude of response was similar or lower compared with low- reactogenicity participants. 

Table of Contents

Table of Contents

Introduction ............................................................................................................................ 1

Methods ................................................................................................................................. 8

Results .................................................................................................................................. 14

Discussion ............................................................................................................................. 19

Tables ................................................................................................................................... 27

Table 1. Baseline Participant Characteristics .................................................................................. 27

Table 2. Longitudinal Associations Between Reaction Score and HAI GMT ..................................... 28

Table 3A-C. Longitudinal Associations Between Alternative Cut Point Reaction Scores and HAI GMT ...................................................................................................................................................... 29

Table 4A-C. Reaction Score and HAI GMT by Study Day.................................................................. 32

Table 5. IM Study Group Reaction Score and H3N2 HAI GMT by Study Day .................................... 35

Table 6A-C. Reaction Score and HAI Titer Fold Change by Study Day .............................................. 36

Table 7. Extreme Reaction Scores and HAI GMT by Study Day........................................................ 39

Table 8. Extreme Reaction Scores and HAI Titer Fold Change by Study Day .................................... 40

Table 9. Reaction Severity and Longitudinal HAI GMT .................................................................... 41

Table 10. Reaction Severity and HAI Titer Fold Change by Study Day ............................................. 42

Table 11. Reaction Duration and Longitudinal HAI GMT ................................................................. 43

Table 12. Reaction Duration and HAI Titer Fold Change by Study Day ............................................ 44

Table 13. Longitudinal Associations Between Reaction Score and HAI Seroprotection ................... 45

Table 14. HAI Seroprotection by Vaccine Route and Day ................................................................ 46

Table 15A-C. Longitudinal Associations Between Alternative Cut Point Reaction Scores and HAI Seroprotection............................................................................................................................... 47

Table 16. Longitudinal Associations Between Reaction Score and HAI Seroconversion................... 50

Table 17A-C. Reaction Score and HAI Seroconversion by Study Day ............................................... 51

Table 18A-C. Longitudinal Associations Between Alternative Cut Point Reaction Scores and HAI Seroconversion .............................................................................................................................. 54

Table 19A-C. Alternative Cut Point Reaction Scores and HAI Seroconversion by Study Day ............ 57

Figures .................................................................................................................................. 63

Figure 1. Conceptual Model ........................................................................................................... 63

Figure 2. Parent Study CONSORT Diagram...................................................................................... 64

Figure 3. Adverse Events by Vaccine Route .................................................................................... 65

Figure 4. Select Local Adverse Events by Time and Vaccine Route .................................................. 66

Figure 5. Correlation Between Adverse Events............................................................................... 67

Figure 6. Reaction Score Univariable Distributions ......................................................................... 68

Figure 7. Reaction Score Bivariable Distributions ........................................................................... 69

Figure 8. H3N2 HAI Titer by Time and Reaction Score..................................................................... 70

References ............................................................................................................................ 71 

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