The Advisory Committee on Immunization Practices recommendation regarding the use of live influenza vaccine: A rejoinder

Vaccine xxx (2017) xxx–xxx

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Commentary

The Advisory Committee on Immunization Practices recommendation regarding the use of live influenza vaccine: A rejoinder Edward A. Belongia a, Ruth A. Karron b, Arthur Reingold c, Emmanuel B. Walter d, Nancy M. Bennett e,⇑ a

Marshfield Clinic Research Institute, Marshfield, WI, United States Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States c School of Public Health, University of California, Berkeley, CA, United States d Department of Pediatrics, Duke University School of Medicine, Durham, NC, United States e Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, United States b

This response is to the recent commentary by Small and Cronin concerning the decision of the U.S. Advisory Committee on Immunization Practices (ACIP) to not recommend the use of live-attenuated influenza vaccine (LAIV) in the U.S. for the 2016–17 influenza season [1]. The authors include the current Chair of the ACIP, and past and present members and chairs of ACIP’s Influenza Working Group, whose deliberations helped inform ACIP in making its decision. ACIP is a federal advisory committee established under the Public Health Service Act (42 U.S.C. § 217a) to provide ‘‘advice and guidance to the Director of the CDC regarding the most appropriate selection of vaccines,” including influenza vaccines, for use in U.S. populations. Before responding to the specific statements in the commentary by Small and Cronin, we will outline briefly how ACIP arrives at its recommendations. ACIP’s deliberations are, by statute, open to the public. All ACIP members are thoroughly vetted for potential conflicts of interest, and a member with potential conflicts related to a given vaccine must recuse her/himself from any vote(s) relating to that vaccine. Preparatory review and deliberation is conducted by Work Groups, each chaired by an ACIP member and comprised of individuals with expertise relating to the vaccine(s) under consideration. Review of evidence related to influenza vaccine is performed by the Influenza Work Group, a standing Work Group of the ACIP. However, all decisions related to influenza vaccine recommendations are voted on by ACIP members during the open ACIP meetings. One of the particular strengths of the ACIP process is the capacity to identify and act upon new evidence in a timely manner. Influenza vaccine composition and vaccine effectiveness estimates vary by year, but consistent patterns of decreased LAIV effectiveness, reported across seasons and by several U.S. influenza vaccine effectiveness surveillance networks, required careful assessment and response. Therefore, in recent seasons, recommendations for the use of LAIV have evolved dynamically based upon available vaccine effectiveness data.

⇑ Corresponding author. E-mail address: [email protected] (N.M. Bennett).

The ACIP first made a preferential recommendation for the use of quadrivalent LAIV (LAIV4) over inactivated influenza vaccine (IIV) in healthy children in 2014 [2]. This recommendation was based on a comprehensive review of studies of the safety and efficacy of trivalent formulations of LAIV and IIV. Because these studies were conducted before the 2009 H1N1 pandemic, none of the vaccines tested contained the A(H1N1)pdm09 strain or a vaccine virus representing a second influenza B lineage. In the U.S., studies conducted by the CDC FLU VE Network, the Department of Defense, and MedImmune showed that, during seasons in which influenza A (H1N1)pdm09 predominated (2013–2014 and 2015–2016), the point estimate for LAIV4 effectiveness was consistently lower relative to IIV for preventing medically attended influenza due to PCR-confirmed H1N1 [https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2016–06/influenza-07-flannery.pdf, Accessed February 25, 2017]. Based upon these data, ACIP made the interim recommendation that LAIV4 should not be used in the U.S. for the 2016–2017 influenza season [3]. Concerns about the effectiveness of the H1N1 component of LAIV were widely recognized: results of the 2013–2014 influenza vaccine effectiveness studies in the U.S. led to replacement of A/California/7/2009 (H1N1) with A/Bolivia/559/2013(H1N1) in 2015–2016, and results of the 2015–2016 influenza vaccine effectiveness studies conducted in the U.S., Europe, and Canada have led to the proposed replacement of A/Bolivia/559/2013(H1N1) with another H1N1 strain in 2017–2018. The results from observational influenza vaccine effectiveness studies have been critically important in the ACIP decision making process. Small and Cronin disparage VE estimates based on the testnegative design (TND) as ‘flawed’ and ‘biased,’ but their comments demonstrate a lack of familiarity with this study design. They criticize the TND because it does not measure indirect protection from vaccination, and they claim the TND is biased against vaccines that prevent transmission. It is true that the TND measures direct rather than indirect protection, but this is not a source of bias. The TND is simply an observational approach to estimate direct protection against PCR confirmed influenza, the same endpoint that is typically used in pre-licensure vaccine trials. The description of the TND analytic method is stated incorrectly by Small and Cronin. In

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Please cite this article in press as: Belongia EA et al. The Advisory Committee on Immunization Practices recommendation regarding the use of live influenza vaccine: A rejoinder. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.06.017

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E.A. Belongia et al. / Vaccine xxx (2017) xxx–xxx

the TND, VE is calculated as 100  (1 adjusted odds ratio) rather than (1 ARV/ARU), and the study design does not assume equal health care seeking behavior in all groups. Small and Cronin also do not cite three published papers that have assessed the validity of the TND and the potential for biased VE estimates [4–6]. These analyses demonstrate that the TND generally yields an unbiased (or minimally biased) VE estimate if two key assumptions are met: (1) the distribution of non-influenza ARI does not vary by influenza vaccination status, and (2) VE does not vary by health care seeking behavior. If these assumptions are met, bias will not occur even if vaccinees and non-vaccinees have different probabilities of seeking care for ARI. However, bias is possible if both illness severity and vaccination status are associated with health care seeking behavior. The magnitude of this bias appears to be modest even under extreme scenarios if true VE is relatively high, and the bias would generally lead to overestimation of true VE [5]. The validity of the TND is also supported by a re-analysis of clinical trial that compared the results of a TND analysis with per-protocol RCT analysis of the same data set and found nearly identical efficacy estimates [7]. Small and Cronin further suggest that a better estimate of vaccine effectiveness could be provided by measurement of influenzaspecific IgG and IgA antibody responses pre- and post-influenza season for recipients of LAIV and IIV, respectively. We are unaware of data to suggest that these measures would provide better estimates. LAIV induces a multifaceted immune response that includes T cells in addition to antibody production, and influenza nasal IgA has been particularly difficult to measure in children [8]. Several comments by Small and Cronin related to the mechanisms of action of LAIV, the biology of influenza virus transmission, and the effects of these upon the TND also warrant attention. Specifically, the assumptions contained in the authors’ Figure 1, which depicts a hypothesized deficit in ascertainment of the effect of LAIV on influenza transmission are questionable. The authors claim that this effect is underestimated because: (1) the induction of sterilizing immunity (‘‘protected from flu infection by LAIV”; green column) among those who did not seek medical aid is not measured, and (2) transmission by those with ‘‘unapparent” [sic] influenza infection is also not measured. Available data contradict both of these hypotheses. The authors appropriately characterize mucosally-delivered LAIV and parenterally-delivered IIV as differing qualitatively and quantitatively in induction of mucosal immune responses; in particular, LAIV has been shown to induce better mucosal IgA responses than IIV [9,10] and better IgA plasmablast responses in adults [11]. However, to our knowledge, there are no human data to suggest that the mucosal antibody induced by LAIV provides sterilizing immunity against influenza infection. Rotavirus vaccines, another example of licensed liveattenuated mucosally delivered vaccines, are effective against rotavirus diarrhea and hospitalization but do not induce sterilizing immunity [12] and it is likely that LAIV behaves in similar fashion. In addition, the authors suggest that substantial potential exists for transmission of influenza from those who do not seek medical care (those with mild or inapparent disease) and who would therefore not be included in the TND. Although shedding can occur prior to symptom onset, longitudinal studies suggest the magnitude of

shedding increases with illness severity. It is likely that most influenza transmission occurs from symptomatic individuals who produce copious amounts of respiratory secretions rather than infected individuals who are asymptomatic. Therefore, at least for influenza A, individuals who might be at greatest risk of transmitting influenza would be captured in the TND. The biologic mechanisms responsible for the reduced effectiveness of the H1N1 component of LAIV4 are being actively investigated. Recent studies conducted by the manufacturer demonstrated that both A/California/7/2009(H1N1) and A/Bolivia/559/2013(H1N1) exhibited reduced replication in a human alveolar cell line and in primary human nasal epithelium air-liquid cultures as well as reduced binding to sialic acid receptors [13]. These data suggest that reduced replicative fitness may have contributed to the observed reduced vaccine effectiveness. Other possible causes of reduced vaccine effectiveness include interference among the 4 LAIV strains, and/or decreased ‘take’ of the H1N1 component of LAIV in U.S children, many of whom have preexisting influenza immunity because of previous vaccination with IIV. Studies to explore these possibilities are ongoing. In conclusion, the ACIP’s decision to not recommend the use of LAIV in the U.S. for the 2016–17 influenza season was supported by available data. LAIV is an important vaccine in the armamentarium for influenza prevention in the U.S. population and the ACIP looks forward to continued research and improvements in its effectiveness. References [1] Small Jr PA, Cronin BJ. The Advisory Committee on Immunization Practices’ controversial recommendation against the use of live attenuated influenza vaccine is based on a biased study design that ignores secondary protection. Vaccine 2017;35(8):1110–2. [2] Grohskopf LA et al. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP) – United States, 2014–15 influenza season. MMWR Morb Mortal Wkly Rep 2014;63(32):691–7. [3] Grohskopf LA et al. Prevention and Control of Seasonal Influenza with Vaccines. MMWR Recomm Rep 2016;65(5):1–54. [4] Foppa IM et al. The case test-negative design for studies of the effectiveness of influenza vaccine. Vaccine 2013;31(30):3104–9. [5] Haber M et al. A probability model for evaluating the bias and precision of influenza vaccine effectiveness estimates from case-control studies. Epidemiol Infect 2015;143(7):1417–26. [6] Jackson ML, Nelson JC. The test-negative design for estimating influenza vaccine effectiveness. Vaccine 2013;31(17):2165–8. [7] De Serres G et al. The test-negative design: validity, accuracy and precision of vaccine efficacy estimates compared to the gold standard of randomised placebo-controlled clinical trials. Euro Surveill 2013;18(37). [8] Ambrose CS et al. The role of nasal IgA in children vaccinated with live attenuated influenza vaccine. Vaccine 2012;30(48):6794–801. [9] Barria MI et al. Localized mucosal response to intranasal live attenuated influenza vaccine in adults. J Infect Dis 2013;207(1):115–24. [10] Clements ML, Murphy BR. Development and persistence of local and systemic antibody responses in adults given live attenuated or inactivated influenza A virus vaccine. J Clin Microbiol 1986;23(1):66–72. [11] Sasaki S et al. Distinct cross-reactive B-cell responses to live attenuated and inactivated influenza vaccines. J Infect Dis 2014;210(6):865–74. [12] Angel J, Steele AD, Franco MA. Correlates of protection for rotavirus vaccines: Possible alternative trial endpoints, opportunities, and challenges. Hum Vaccin Immunother 2014;10(12):3659–71. [13] Ambrose CS, Bright H, Mallory R. Letter to the editor: Potential causes of the decreased effectiveness of the influenza A(H1N1)pdm09 strain in live attenuated influenza vaccines. Euro Surveill 2016;21(45).

Please cite this article in press as: Belongia EA et al. The Advisory Committee on Immunization Practices recommendation regarding the use of live influenza vaccine: A rejoinder. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.06.017