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

Simple Summary Vaccinated mother pigs can pass vaccine protection (immunity) onto their offspring, but in the case of influenza, the benefit is not clear. Influenza viruses evolve rapidly and can sometimes change their appearance to the point of becoming a new stain that evades a pig's immune defenses. It is believed that matching the vaccine to the virus is important for protection. To predict if a vaccine is protective it is, therefore, also important to know how closely it matches the influenza strain or strains circulating in the herd. For the first time, we apply the methods of evidence-based medicine to understand if vaccinating sows results in the protection of their piglets from influenza. We were only interested in studies where the researcher knew if the vaccine matched the infecting virus. These types of studies are called challenge trials because researchers controlled both the vaccines used in the mother pigs and the strain of influenza viruses used to infect the piglets. We looked at scientific studies published over twenty years and considered many ways to measure protection. We found piglets from vaccinated sows took a little bit longer to shed the virus if they became infected and that less virus was found in piglets where their mother's vaccine matched the virus used to infect the piglet. In modern commercial farms, however, piglets are often exposed back-to-back or at the same time to the same, or more often, to more than one strain of influenza. Also, viruses behave differently in herds than they do in small studies because the number of pigs in a herd is many times greater. Because most studies involved simple exposures in small groups of pigs and only one small study looked at a back-to-back exposure with the same strain of influenza, it is difficult to know if our findings can be further extended into the real world. Despite this, the body of research was useful to show the importance of matching. We also learned that additional research is still needed and importantly, that there is room for improvement in how influenza vaccine studies in pigs are reported. Influenza vaccine research is complex in pigs and it is important to understand the type or types of virus strains involved in each study. Future research is needed where researchers are able to identify all infecting strains of influenza and the piglets experience real-world influenza virus exposures.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 1/2 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.