Critical appraisal

Li et al. 2021. NPJ Vaccines. [1]

As discussed in the weblog, the diminished vaccine response observed in the elderly population carries significant consequences for society. These consequences include escalated healthcare costs attributable to the heightened infection risk among older individuals, resulting in an increased incidence of clinical admissions. This underscores the need to explore resolutions for the challenge of reduced vaccine efficacy in the elderly demographic. In this context, Li et al. aimed at identifying two vaccines employing alternative immunological strategies distinct from the conventional influenza vaccination, with the goal of identifying the most effective vaccine for the elderly population of Hong Kong. [1]

The following paragraphs  of this critical appraisal provide a concise summary of the research, elucidating the study design, presenting the findings while using the JAMA-criteria to illuminate its validity. [2]

Summary

The study aimed to investigate whether vaccines with higher antigen content or adjuvants could effectively enhance the vaccination response in older adults. Specifically, the standard influenza vaccine, referred to as S-IIV, was compared to three enhanced vaccines: MF59-adjuvanted IIV (A-eIIV), high-dose IIV (H-eIIV), and recombinant HA IIV (R-eIIV). 

 

In a previous study, they demonstrated that the three enhanced vaccines gave higher Hemagglutination Inhibition Antibody (HAI) titers and generated more HAI antibodies against the influenza virus compared to the S-IIV vaccine. The HAI titer measures the extent to which serum must be diluted to prevent hemagglutination of erythrocytes as a result of influenza infection. A higher HAI titer indicates better protection. However, this parameter only represents a fraction of the overall immune response.

 

The aim of this study was to further explore, in addition to HAI, whether other humoral and cellular parameters of the immune response are effectively affected by the enhanced vaccines, with particular focus on responses to the Influenza subtype A(H3N2). 

Study design and method

This randomized controlled trial was performed by the University of Hong Kong. Between October 2017 and January 2018, 800 subjects were recruited and found eligible for the study. However, any inclusion or exclusion criteria remained unknown through the article. The age of the group was between 65 and 82 years. All 800 participants were randomized 1:1:1:1, in groups of 200, to either receive S-IIV, A-eIIV, H-eIIV or R-eIIV. Only a small fraction, 124 participants, of these 800 subjects were ultimately analyzed. The remaining 676 participants failed to hand in new blood samples and therefore, the analysis could not be finished. This non-compliance with study requirements or inadequate investigator follow-up results in a reduction of the study’s statistical power due to a smaller sample size. 

 

There were no statistically significant differences in the baseline characteristics. This suggests that the groups were balanced with respect to age, gender, earlier vaccinations or factors as smoking or comorbidities. It helps to ensure the comparability of the groups and reduces the potential for confounding to impact the study’s outcome. The only difference among the four study groups was the administration of the experimental treatment. This increases the power to detect a significant treatment-related outcome. 

However, it is noteworthy that the study did not provide elaboration on the blinding procedures for both participants and practitioners. Lack of blinding can influence the perception and behavior of both groups and therefore, possibly negatively affect the study’s validity. 

Results

Li et al. found that enhanced vaccines (A-eIIV, H-eIIV and R-eIIV) consistently outperformed standard-dose vaccination across the rane of immune parameters that were analyzed in this study. Firstly A-eIIV demonstrated an early increase (day 7) in high-avidity antibodies, but not long-term maintenance. Secondly, an increase in activated TFH1 cells and peak in plasma blasts was observed at day 7 post vaccination with A-eIIV and H-eIIV. There was no difference in magnitude of recruitment of the TFH1 cells. Potentially, the increase in activated TFH1 cells can overcome age-related impairment of the cells. A-eIIV and R-eIIV are associated with a more cytokine-secreting CD4- and 8+ T-cell response. Elevated HAI titers were found in these vaccines, suggesting more protection against the Influenza virus. Lastly, frequent vaccination, with standard or enhanced vaccines, blunted the TFH1 cell recruitment, but enhanced antibody avitidy, especially with H-eIIV.

 

Notably, the study did not present statistical significance or provide clear numerical values of the results. It relied on the graphical representations to illustrate treatment effects. Therefore, the exact treatment effect is unclear with unknown numbers. 

Conclusion

In conclusion, Li et al. offered valuable insights into the immunogenicity of seasonal influenza vaccines in older adults. The consistent outperformance of enhanced vaccines over standard-dose vaccination across numerous immune parameters, like antibody-avidity and activation and recruitment of TFH-cells, underscores the potential benefits for this vulnerable population. However, the lack of statistically significant and clear numerical treatment effects in the text, calls for improved reporting practices in future studies. In addition to the unclear results, the validity is also questionable as there was no elaboration on the blinding of the participants or investigators and an incredibly high attrition rate due to low compliance. To advance our understanding of vaccine effectiveness in older adults and development of universal influenza vaccines, more research is needed with clear insights in the study set-up and blinding. 

Literature

[1]     Li APY, Cohen CA, Leung NHL, Fang VJ, Gangappa S, Sambhara S. Immunogenicity of standard, high-dose, MF59- adjuvanted, and recombinant-HA seasonal influenza vaccination in older adults. NPJ Vaccines. 2021 Feb 16; 6(1): 25. 

[2]     Guyatt GH, Sackett DL, Cook DJ. User’s Guides to the Medical Literature: How to Use an Article About Therapy or Prevention; Are the Results of the Study Valid?. JAMA. 1993 Dec 1; 270(21): 2598-2601.