Does Vaccine-Induced Maternally-Derived Immunity Protect Swine Offspring against Influenza a Viruses? A Systematic Review and Meta-Analysis of Challenge Trials from 1990 to May 2021

Abstract

It is unclear if piglets benefit from vaccination of sows against influenza. For the first time, methods of evidence-based medicine were applied to answer the question: "Does vaccine-induced maternally-derived immunity (MDI) protect swine offspring against influenza A viruses?". Challenge trials were reviewed that were published from 1990 to April 2021 and measured at least one of six outcomes in MDI-positive versus MDI-negative offspring (hemagglutination inhibition (HI) titers, virus titers, time to begin and time to stop shedding, risk of infection, average daily gain (ADG), and coughing) (n = 15). Screening and extraction of study characteristics was conducted in duplicate by two reviewers, with data extraction and assessment for risk of bias performed by one. Homology was defined by the antigenic match of vaccine and challenge virus hemagglutinin epitopes. Results: Homologous, but not heterologous MDI, reduced virus titers in piglets. There was no difference, calculated as relative risks (RR), in infection incidence risk over the entire study period; however, infection hazard (instantaneous risk) was decreased in pigs with MDI (log HR = -0.64, 95% CI: -1.13, -0.15). Overall, pigs with MDI took about a ½ day longer to begin shedding virus post-challenge (MD = 0.51, 95% CI: 0.03, 0.99) but the hazard of infected pigs ceasing to shed was not different (log HR = 0.32, 95% CI: -0.29, 0.93). HI titers were synthesized qualitatively and although data on ADG and coughing was extracted, details were insufficient for conducting meta-analyses. Conclusion: Homology of vaccine strains with challenge viruses is an important consideration when assessing vaccine effectiveness. Herd viral dynamics are complex and may include concurrent or sequential exposures in the field. The practical significance of reduced weaned pig virus titers is, therefore, not known and evidence from challenge trials is insufficient to make inferences on the effects of MDI on incidence risk, time to begin or to cease shedding virus, coughing, and ADG. The applicability of evidence from single-strain challenge trials to field practices is limited. Despite the synthesis of six outcomes, challenge trial evidence does not support or refute vaccination of sows against influenza to protect piglets. Additional research is needed; controlled trials with multi-strain concurrent or sequential heterologous challenges have not been conducted, and sequential homologous exposure trials were rare. Consensus is also warranted on (1) the selection of core outcomes, (2) the sizing of trial populations to be reflective of field populations, (3) the reporting of antigenic characterization of vaccines, challenge viruses, and sow exposure history, and (4) on the collection of non-aggregated individual pig data.

Keywords: influenza A viruses of swine; influenza vaccines; maternally derived immunity; meta-analysis; systematic review.

Figure 1

PRISMA flowchart: Flow of citations through search and relevance screening processes to identify IAV-S vaccine-induced MDI challenge trial research involving swine offspring from literature published between 1990 and 2021; PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses; WoS = Web of Science; AASV = AASV Swine Information Library; MDI= IAV-S vaccine-induced maternally-derived immunity; in-pig = pig level study unit; ^† Publications identified in prior scoping review [60]; Effect size defined as difference in outcomes in MDI-positive piglet offspring (treatment group) versus MDI-negative piglet offspring (control group); Each publication may include >1 study and each study may include >1 treatment-control comparison (i.e., multi-armed studies); PRISMA flowchart template modified from Page et al. [84].

Figure 2

Piglet offspring age (weeks) at occurrence of important study events for each of 16 IAV-S vaccine-induced MDI challenge trials [61,69,83,85,86,87,88,89,90,91,93,94]. *Pyo et al. [83] included descritptively only but no outcome data were extracted.

Figure 3

Maternal IAV-S exposure history for sows in 16 vaccine-induced MDI challenge trials: Pre-farrowing IAV-S vaccination schedules and natural virus exposure [61,69,83,85,86,87,88,89,90,91,93,94].

Figure 4

Sub-group meta-analysis forest plot of effects of IAV-S vaccine-induced MDI on relative risk (RR) of infection in IAV-S challenged piglets: sub-grouping by sow vaccine antigenic homology with challenge virus. Study = MDI comparisons at the level of the trial and at the level of the treatment arm comparisons versus a control (in cases where trials include multi-arm comparisons); studies are label following the convention of [Author]-[Trial #]_[treatment arm comparison #], [year of publication]; for study citations refer to Table 1 as listed by author and year of publication. Meta-analysis sub-grouped by MDI strain where MDI_strain = antigenic match of the maternal vaccine composition to the challenge virus (heterologous or homologous); MDI = maternally-derived immunity; MDI-positive = experimental (treatment) groups of offspring of IAV-S vaccinated dams; MDI-negative = control groups of offspring from non-vaccinated, IAV-S negative control dams; studies with concurrent IAV-S vaccination of piglets (Piglet Vx) were identified similarly as strain homologous (hom) or heterologous (het) with the challenge virus; effect = incidence of infection; effect size is the risk ratio; solid vertical line at 0 equals the point of no difference in effects of MDI-positive versus MDI-negative groups (i.e., log risk ratio = 0) and points to the right of the line indicate MDI increases the effect in the treatment group; I² 95% uncertainty interval (lower bound, upper bound) = (0.00, 77.5); effect sizes are represented by squares with size proportional to their weighted contribution to the summary effect measure; weighted contribution is shown as a % in columns on the right; summary effects sizes are represented by diamonds [61,89,91,94].

Figure 5

Sub-group meta-analysis forest plot of effects of IAV-S vaccine-induced MDI on virus titers in IAV-S challenged piglets: sub-grouping by sow vaccine homology with challenge virus. Composite effect sizes adjusted using estimate of high (h) correlation between repeated measures–comparisons with concurrently vaccinated offspring were included in the analysis. Study = MDI comparisons at the level of the trial and at the level of the treatment arm comparisons versus a control (in cases where trials include multi-arm comparisons); studies are label following the convention of [Author]-[Trial #]_[treatment arm comparison #], [year of publication]; for study citations refer to Table 1 as listed by author and year of publication.MDI = maternally derived immunity in offspring as induced through vaccination of dams against IAV-S. Meta-analysis sub-grouped by MDI status; Strain homologous = viral components of sow vaccine match the strain of the challenge virus; Strain heterologous = IAV-s virus antigenic components of the sow vaccine differ at the strain level from the challenge virus; Not defined = the IAV-S antigenic components of the maternal vaccine were not defined. n= total number of piglets in each treatment-control comparison; Challenge age is piglet days of age at challenge. Treatment-control comparisons involving concurrent IAV-S vaccination of piglets were included in meta-analysis; match of piglet vaccine stain with the challenge virus identified accordingly under the column heading Piglet Vx as hom (homologous) or Het (heterologous). Effect is mean virus titer (measured from nasal swab samples using virus isolation methods in all studies except for Bosworth et al. –virus quantified by PCR). Effect size is Hedges’ g, (standardized mean difference corrected for small sample size bias) calculated as a composite of effect sizes derived by collapsing first across homologous treatment arms and then across repeated time points, with pooled variances adjusted to account for assumed high (h) correlation of measures (0.75) from time point to time point. Columns on the right under the heading of Estimate are values and their 95% confidence intervals for the corresponding effect sizes and summary effect sizes. Effect sizes are represented by squares with size proportional to their weighted contribution to the summary effect size. Summary effects sizes are represented by diamonds. The dotted vertical line indicates a standardized mean difference of 0 (no effect difference between MDI-positive and MDI-negative groups) and points to the right of the line indicate MDI increases mean virus titers in offspring. I² 95% uncertainty interval (lower bound, upper bound) = (51.21, 89.35). Refs [69,85,86,87,88,89].

Figure 6

Subgroup meta-analysis forest plot of effects of IAV-S vaccine-induced MDI on likelihood (Log HR) of IAV-S challenged offspring to begin shedding virus: sub-grouping by sow vaccine antigenic homology with challenge virus. Study = MDI comparisons at the level of the trial and at the level of the treatment arm compari-sons versus a control (in cases where trials include multi-arm comparisons); studies are label following the convention of [Author]-[Trial #]_[treatment arm comparison #], [year of publica-tion]; for study citations refer to Table 1 as listed by author and year of publication.MDI = maternally derived immunity in offspring as induced through IAV-S vaccination of dams. Meta-analysis sub-grouped by MDI status; Strain homologous (hom) = viral components of sow vaccine match the challenge virus strain; Strain heterologous (het)= IAV-S virus antigenic components of the sow vaccine differ at the strain level from the challenge virus; effect is the hazard (the instantaneous rate of a first detection of virus in nasal swabs at any point in time during the post-challenge study period); effect size is the log of the hazard ratio (HR) between treatment and control groups as derived from Cox proportional hazard analysis; the dotted vertical line at 0 indicates the point of no difference in effects between the treatment and control groups; points to the right of the line indicate MDI increases the effect in the treatment group; I² 95% uncertainty interval (lower bound, upper bound) = (0.00, 89.08); effect sizes are represented by squares with size proportional to their weighted contribution to the summary effect measure; values in the columns on the right hand side equal the weighted contribution is shown as a %, effect sizes and the summary effect sizes under the header of Estimate with their corresponding 95% confidence intervals [95% CI]; summary effects sizes are represented by diamonds [61,89,91].

Figure 7

Subgroup meta-analysis forest plot of effects of IAV-S vaccine-induced MDI on difference in mean time (days) for IAV-S challenged offspring to begin shedding virus: sub-grouping by sow vaccine homology with challenge virus. Study = MDI comparisons at the level of the trial and at the level of the treatment arm com-pari-sons versus a control (in cases where trials include multi-arm comparisons); studies are la-bel following the convention of [Author]-[Trial #]_[treatment arm comparison #], [year of pub-lica-tion]; for study citations refer to Table 1 as listed by author and year of publication. MDI = maternally derived immunity in offspring as induced through IAV-S vaccination of dams. Meta-analysis sub-grouped by MDI status; Strain homologous (hom) = viral components of sow vaccine match the challenge virus strain; Strain heterologous (het)= IAV-S virus antigenic components of the sow vaccine differ at the strain level from the challenge virus; effect is mean time (days) for detection of virus in nasal swabs post-challenge; effect size is differences in mean time of MDI-positive vs. MDI-negative pigs to start shedding; the dotted vertical line indicates a mean difference of 0 (no difference between groups), points to the right indicates pigs with MDI take longer to begin shedding virus. I² 95% uncertainty interval (lower bound, upper bound) = (98.41, 99.90); effect sizes are represented by squares with size proportional to their weighted contribution to the summary effect size; values in the columns on the right hand side equal the weighted contribution is shown as a %, effect sizes and the summary effect sizes under the header of Estimate with their corresponding 95% confidence intervals [95% CI]; summary effects sizes are represented by diamonds [61,89,91].

Figure 8

Subgroup meta-analysis forest plot of effects of IAV-S vaccine-induced MDI on the mean difference in time (days) for IAV-S challenged offspring to begin shedding virus–removing a single outlier effect size: sub-grouping by sow vaccine homology with challenge virus. Study = MDI comparisons at the level of the trial and at the level of the treatment arm com-pari-sons versus a control (in cases where trials include multi-arm comparisons); studies are la-bel following the convention of [Author]-[Trial #]_[treatment arm comparison #], [year of pub-lica-tion]; for study citations refer to Table 1 as listed by author and year of publication. MDI = maternally derived immunity in offspring as induced through IAV-S vaccination of dams. Meta-analysis sub-grouped by MDI status; Strain homologous (hom) = viral components of sow vaccine match the challenge virus strain; Strain heterologous (het)= IAV-S virus antigenic components of the sow vaccine differ at the strain level from the challenge virus; effect is mean time (days) for detection of virus in nasal swabs post-challenge; effect size is differences in mean time of MDI-positive vs. MDI-negative pigs to start shedding; the dotted vertical line indicates a mean difference of 0 (no difference between groups), points to the right indicates pigs with MDI take longer to begin shedding virus; a single study with an effect size on the extreme right of the plot was removed from the analysis (Allerson et al., 2013.2 MDI hom) effect size comparing the MDI homologous piglets (MD = 10.98, 95% CI: 10.01–11.96); I² 95% uncertainty interval (lower bound, upper bound) = (98.41, 99.90); effect sizes are represented by squares with size proportional to their weighted contribution to the summary effect size; values in the columns on the right-hand side equal the weighted contribution is shown as a %, effect sizes and the summary effect sizes under the header of Estimate with their corresponding 95% confidence intervals [95% CI]; summary effects sizes are represented by diamonds [61,89,91].

Figure 9

Subgroup meta-analysis forest plot of effects of IAV-S vaccine-induced MDI on the log hazard ratio (Log HR) of IAV-S challenged offspring for stopping virus shedding: sub-grouping by sow vaccine homology with challenge virus. Study = MDI comparisons at the level of the trial and at the level of the treatment arm com-pari-sons versus a control (in cases where trials include multi-arm comparisons); studies are la-bel following the convention of [Author]-[Trial #]_[treatment arm comparison #], [year of pub-lica-tion]; for study citations refer to Table 1 as listed by author and year of publication. MDI = maternally derived immunity in offspring as induced through IAV-S vaccination of dams. Meta-analysis sub-grouped by MDI status; Strain homologous (hom) = viral components of sow vaccine match the challenge virus strain; Strain heterologous (het)= IAV-S virus antigenic components of the sow vaccine differ at the strain level from the challenge virus; effect is the hazard (the instantaneous rate in virus positive piglets of ceasing to shed virus at any point during the post-challenge study period); effect size is the log of the hazard ratio (HR) as derived from cox proportional hazard analysis; the dotted vertical line at 0 indicates the point of no difference (log HR = 0) and points to the right of the line indicate MDI increases the effect in the treatment group; I² 95% uncertainty interval (lower bound, upper bound) = (3.64, 89.69); effect sizes are represented by squares with size proportional to their weighted contribution to the summary effect measure; values in the columns on the right hand side equal the weighted contribution is shown as a %, effect sizes and the summary effect sizes under the header of Estimate with their corresponding 95% confidence intervals [95% CI]; summary effects sizes are represented by diamonds [61,89,91].

Figure 10

Subgroup meta-analysis forest plot of effects of IAV-S vaccine-induced MDI on the mean difference (days) in time for infected IAV-S challenged offspring to stop shedding virus: sub-grouping by sow vaccine homology with challenge virus. Study = MDI comparisons at the level of the trial and at the level of the treatment arm com-pari-sons versus a control (in cases where trials include multi-arm comparisons); studies are la-bel following the convention of [Author]-[Trial #]_[treatment arm comparison #], [year of pub-lica-tion]; for study citations refer to Table 1 as listed by author and year of publication. MDI = maternally derived immunity in offspring as induced through IAV-S vaccination of dams. Meta-analysis sub-grouped by MDI status; Strain homologous (hom) = viral components of sow vaccine match the challenge virus strain; Strain heterologous (het)= IAV-S virus antigenic components of the sow vaccine differ at the strain level from the challenge virus; effect is mean number of days virus is detected in nasal swabs of infected piglets; effect size is difference in the mean days MDI-positive pigs shed virus versus MDI-negative pigs; the dotted line indicates a mean difference of 0 (no difference between MDI-positive and MDI-negative groups in mean days shedding); points to the right of the line indicate that pigs with MDI shed virus longer; I² 95% uncertainty interval (lower bound, upper bound) = (47.40 96.61); effect sizes are represented by squares with size proportional to their weighted contribution to the summary effect measure; values in the columns on the right hand side equal the weighted contribution is shown as a %, effect sizes and the summary effect sizes under the header of Estimate with their corresponding 95% confidence intervals [95% CI]; summary effects sizes are represented by diamonds [61,89,91].