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Field safety of a modified-live, cold-adapted intranasal equine influenza vaccine (HESKA™ Flu Avert™ I.N. vaccine) in horses
licensed to practice in their respective states. Before initiating the study, the study coordinator from Heska Corporation visited each study site and provided in-depth training to principal investigators and all staff involved in the study at the respective site. This training included instruction regarding storage W. David Wilson, BVMS, MS, MRCVS; ~ and reconstitution of the lyophilized and David Robinson, DVM2 vaccine, assembly and proper filling of the applicator with vaccine, technique for This report presents the findings vaccine administration, and appropriof a field study to evaluate the safety ate recording and reporting of horse of a modified-live, cold-adapted equine identification, vaccine use, and adverse influenza vaccine (HESY-,E.~TMFlu AvertT M effects. I.N. vaccine) administered intranasally to A minimum age restriction of 3 healthy horses. This stud~ fulfilled one of months was imposed in selection of study the USDA requirements for the licensure subjects and a subgroup of horses were of the vaccine. The objectives of this required to be at or below "minimum study were, therefore: 1) to determine the age" (11 months of age, the minimum age safety of the vaccine following intranasal included on the vaccine label). Healthy administration of a single dose to healthy horses ranging in age from 3 months to horses, 2) to fulfill USDA field safety study 30 years were, therefore, included in the requirements, 3) to collect information study. Of the 435 horses enrolled in the regarding product use and administration, study, 106 were 15 months or less in age, and 4) to collect blood samples for later including 53 that were 11 months-old or assessment of the serological response less. The study subjects included mares, to vaccination. stallions, colts, geldings, and fillies of a variety of breeds. Of the mares included in the study, 11 were reported to be pregnant MATERIALS AND METHODS at the time of vaccination. All horses were identified by an appropriate method Four hundred thirty-five client(name, brand, tattoo, numbered neck band, owned horses at seven study sites in etc.) to allow accurate identification and California, Colorado (2 sites), Kansas, monitoring throughout the study period. Kentucky, Nebraska, and Minnesota The modified-live, cold-adapted were enrolled in the study. Study sites equine influenza vaccine (Flu Avert T M included private veterinary practices I.N. vaccine) used in the study was and large animal field service practices produced and supplied by H e s k a at universities. All investigators were Corporation. Each study site received an approximately equal number of doses Authors' Addresses:1Department of Medicine of each of two serials, identified by and Epidemiology, School of Veterinary Medicine, different colored caps and labels on vials University of California, Davis, CA 95616. 2Heska Corporation, 1825 Sharp Point Drive, Fort Collins, of vaccine. Each investigator was asked CO 8O525. Acknowledgements:The authors wish to thank to use an equal number of each serial in the following for participating in the field trial their investigation. Investigators were investigations: Charles D. Vail, DVM, Littleton, instructed to reconstitute and administer CO; Lowell Smalley, DVM, Omaha, NE; Thomas Juergens, DVM, Elk River, MN; Robert Holland, the lyophilized experimental vaccine DVM, Lexington, KY; Kevin Hankins, DVM, according to directions and observe the Manhattan, KS
FIELD SAFETY OF A MODIFIED-LIVE, COLD-ADAPTED INTRANASAL EQUINE INFLUENZA VACCINE (HESKA TM FLU AVERT TM I.N. VACCINE) IN HORSES
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animals for evidence of adverse reactions within a few hours following vaccination and then daily for 14 days. Only "healthy horses" lacking overt evidence of disease were included in the study. Investigators were instructed to report any adverse event regardless of whether or not it was believed to have been caused by the vaccine. While investigators were instructed to report any perceived adverse event, they were asked to pay particular attention to acute or delayed onset of signs such as coughing, abnormal nasal discharge, abnormal respiratory rate and character, sneezing, altered behavior, lethargy and abnormal appetite. In addition, investigators were asked to record the rectal temperature of any horse showing signs suggestive of an adverse event.
RESULTS With few exceptions, horses generally tolerated intranasal administration of the vaccine well. The applicator was found tO be sufficiently pliable as to be atraumatic but stiff enough to allow it to be directed into the ventral nasal meatus. Most horses raised their heads and showed a typical phlegmon response (curling of the Upper lip and an elevated and outstretched head and neck) of variable duration immediately after administration of the vaccine. This response appeared to contribute to good retention of the vaccine within the nasal passage of most horses. Apart from the phlegmon response and the variable but small amount of vaccine that dripped from the nostril of some horses immediately after administration of the vaccine, perceived adverse events were not noted within the few hours following vaccination. The overall incidence of suspected adverse events was low, being observed in a total of 27 (6.2%) of the 435 horses (Table 1). The mo st frequently observed adverse event was nasal' discharge (22/435; 5.1%), followed by ocular discharge (3/435; 0.7%) and cough (2/435; 0.5%). With the exception of the findings at one study site (site B),
JOURNAL OF EQUINE VETERINARY SCIENCE
Table
nasal discharge, when it occurred, was typically observed transiently within 24 to 48 hours after vaccination, was serous in character, scant in quantity, and present only in the nostril into which the vaccine was administered. The most severe adverse reaction noted in the study was transient urticaria in 3 (0.68%) horses. Most of the adverse clinical events were reported from one study site (site B) which contributed less than 20% of the enrollees in this study (Table 2). The principal investigator at this site noted that non-vaccinated horses kept under similar conditions at the same facility had a similar incidence-of slight serous nasal and ocular discharge and that the intense daily observation and recording protocol over the 14 days of this study contributed to a high rate of detection of signs that would not otherwise have been of concem. Based on his experience at this facility, the investigator at site B concluded that both the vaccinates and non-vaccinates had a "normal" seasonal incidence of slight serous nasal and/or ocular discharge. The combined incidence of adverse events for all study sites other than site B was less than 1% (Table 3). DISCUSSION Of the adverse events reported in this study, it is reasonable to conclude that transient mild serous nasal or ocular discharge was related to intranasal administration of the modified-live cold-adapted influenza vaccine in a low percentage of horses. While the higher incidence of these signs following vaccination at one study site (site B) may reflect a real difference in the incidence of adverse events at that site versus all others, it is more likely that the difference was due to the criteria and methods used by the investigator at that site to categorize and record clinical data. The finding that 10
1. Adverse
Event type Nasal discharge Ocular discharge Coughing
events at all test sites* Ages 3-11 mon 53 horses no. frequency 2 0 0
Ages 3-15 mon 106 horses no. frequency
3.8% 0.0% 0.0%
8 0 1
7.5% 0.0% 0.9%
Ages 3 mon- 30 yrs 435 horses no. frequency 22 3 2
5.1% 0.7% 0.5%
*7 test sites (including site B) Table 2 . Adverse events at site B
Event type Nasal discharge Ocular discharge Coughing
Ages 3-11 mon 4 horses no. frequency 1 0 0
Ages 3-15 mon 21 horses no. frequency
25.0% 0.0% 0.0%
7 0 1
33.3% 0.0% 4.8%
Ages 3 mon- 30 yrs 69 horses no. frequency 19 3 2
27.5% 4.3% 2.9%
Table 3. Adverse events at all sites, except site B Ages 3-11 mon
Ages 3-15 mon
AQ hnrr162
Event type Nasal discharge Ocular discharge Coughing
no. frequency 1 0 0
Ages 3 mon- 30 yrs
RF, hnr~=~
2.0% 0.0% 0.0%
no. frequency 1 0 0
a similar incidence of transient serous nasal or ocular nasal discharge occurred in horses that were not vaccinated with Flu Avert T M I.N. vaccine at this site suggests that many of the reported adverse events may not have been related to administration of the vaccine. In addition, it could be reasonably interpreted from the information provided by the investigator regarding horses with clinical signs of a suspected adverse event, that signs may have been within the spectrum of "normal" rather than being an adverse event. ~qlile a low incidence of urticaria may prove to be a potential side-effect resulting from administration of the vaccine, a direct link between vaccination and occurrence of this adverse event could not be identified in this study. No adverse events were noted in the 11 pregnant mares included in the study, except that one delivered a lethal white foal. Since this condition is known to be a genetic lethal syndrome, it is unlikely that there was any causal relationship attributable
1.2% 0.0% 0.0%
RRR hnr.~A.~
no. frequency 3 0 0
0.8% 0.0% 0.0%
to the experimental vaccine. The low incidence of adverse events associated with intranasal administration of Flu Avert T M I.N. vaccine in this extensive field safety study indicates that this vaccine is safe for administration to healthy horses 11 months of age and older under field conditions. Similarly, other studies performed with Flu Avert T M I.N. vaccine (back-passage, immunogenicity, and duration of immunity studies) showed virtually no evidence of post-vaccination reactions. Of the reported adverse events following vaccination, mild and transient nasal or ocular discharge can be anticipated in a low percentage of horses vaccinated under field conditions. These signs typically resolve within 1 to 2 days without treatment and are sufficiently mild; owners would be unlikely to seek assistance from their veterinarian. Regardless, owners should be warned about the possible occurrence of transient nasal or ocular discharge at the time of administration of the vaccine.
JOURNAL OF EQUINE VETERINARY SCIENCE
FIELD SAFETY OF A MODIFIED-LIVE, COLD-ADAPTED INTRANASAL EQUINE INFLUENZA VACCINE (HESKA TM FLU AVERT TM I.N. VACCINE) IN HORSES
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animals for evidence of adverse reactions within a few hours following vaccination and then daily for 14 days. Only "healthy horses" lacking overt evidence of disease were included in the study. Investigators were instructed to report any adverse event regardless of whether or not it was believed to have been caused by the vaccine. While investigators were instructed to report any perceived adverse event, they were asked to pay particular attention to acute or delayed onset of signs such as coughing, abnormal nasal discharge, abnormal respiratory rate and character, sneezing, altered behavior, lethargy and abnormal appetite. In addition, investigators were asked to record the rectal temperature of any horse showing signs suggestive of an adverse event.
RESULTS With few exceptions, horses generally tolerated intranasal administration of the vaccine well. The applicator was found tO be sufficiently pliable as to be atraumatic but stiff enough to allow it to be directed into the ventral nasal meatus. Most horses raised their heads and showed a typical phlegmon response (curling of the Upper lip and an elevated and outstretched head and neck) of variable duration immediately after administration of the vaccine. This response appeared to contribute to good retention of the vaccine within the nasal passage of most horses. Apart from the phlegmon response and the variable but small amount of vaccine that dripped from the nostril of some horses immediately after administration of the vaccine, perceived adverse events were not noted within the few hours following vaccination. The overall incidence of suspected adverse events was low, being observed in a total of 27 (6.2%) of the 435 horses (Table 1). The mo st frequently observed adverse event was nasal' discharge (22/435; 5.1%), followed by ocular discharge (3/435; 0.7%) and cough (2/435; 0.5%). With the exception of the findings at one study site (site B),
JOURNAL OF EQUINE VETERINARY SCIENCE
Table
nasal discharge, when it occurred, was typically observed transiently within 24 to 48 hours after vaccination, was serous in character, scant in quantity, and present only in the nostril into which the vaccine was administered. The most severe adverse reaction noted in the study was transient urticaria in 3 (0.68%) horses. Most of the adverse clinical events were reported from one study site (site B) which contributed less than 20% of the enrollees in this study (Table 2). The principal investigator at this site noted that non-vaccinated horses kept under similar conditions at the same facility had a similar incidence-of slight serous nasal and ocular discharge and that the intense daily observation and recording protocol over the 14 days of this study contributed to a high rate of detection of signs that would not otherwise have been of concem. Based on his experience at this facility, the investigator at site B concluded that both the vaccinates and non-vaccinates had a "normal" seasonal incidence of slight serous nasal and/or ocular discharge. The combined incidence of adverse events for all study sites other than site B was less than 1% (Table 3). DISCUSSION Of the adverse events reported in this study, it is reasonable to conclude that transient mild serous nasal or ocular discharge was related to intranasal administration of the modified-live cold-adapted influenza vaccine in a low percentage of horses. While the higher incidence of these signs following vaccination at one study site (site B) may reflect a real difference in the incidence of adverse events at that site versus all others, it is more likely that the difference was due to the criteria and methods used by the investigator at that site to categorize and record clinical data. The finding that 10
1. Adverse
Event type Nasal discharge Ocular discharge Coughing
events at all test sites* Ages 3-11 mon 53 horses no. frequency 2 0 0
Ages 3-15 mon 106 horses no. frequency
3.8% 0.0% 0.0%
8 0 1
7.5% 0.0% 0.9%
Ages 3 mon- 30 yrs 435 horses no. frequency 22 3 2
5.1% 0.7% 0.5%
*7 test sites (including site B) Table 2 . Adverse events at site B
Event type Nasal discharge Ocular discharge Coughing
Ages 3-11 mon 4 horses no. frequency 1 0 0
Ages 3-15 mon 21 horses no. frequency
25.0% 0.0% 0.0%
7 0 1
33.3% 0.0% 4.8%
Ages 3 mon- 30 yrs 69 horses no. frequency 19 3 2
27.5% 4.3% 2.9%
Table 3. Adverse events at all sites, except site B Ages 3-11 mon
Ages 3-15 mon
AQ hnrr162
Event type Nasal discharge Ocular discharge Coughing
no. frequency 1 0 0
Ages 3 mon- 30 yrs
RF, hnr~=~
2.0% 0.0% 0.0%
no. frequency 1 0 0
a similar incidence of transient serous nasal or ocular nasal discharge occurred in horses that were not vaccinated with Flu Avert T M I.N. vaccine at this site suggests that many of the reported adverse events may not have been related to administration of the vaccine. In addition, it could be reasonably interpreted from the information provided by the investigator regarding horses with clinical signs of a suspected adverse event, that signs may have been within the spectrum of "normal" rather than being an adverse event. ~qlile a low incidence of urticaria may prove to be a potential side-effect resulting from administration of the vaccine, a direct link between vaccination and occurrence of this adverse event could not be identified in this study. No adverse events were noted in the 11 pregnant mares included in the study, except that one delivered a lethal white foal. Since this condition is known to be a genetic lethal syndrome, it is unlikely that there was any causal relationship attributable
1.2% 0.0% 0.0%
RRR hnr.~A.~
no. frequency 3 0 0
0.8% 0.0% 0.0%
to the experimental vaccine. The low incidence of adverse events associated with intranasal administration of Flu Avert T M I.N. vaccine in this extensive field safety study indicates that this vaccine is safe for administration to healthy horses 11 months of age and older under field conditions. Similarly, other studies performed with Flu Avert T M I.N. vaccine (back-passage, immunogenicity, and duration of immunity studies) showed virtually no evidence of post-vaccination reactions. Of the reported adverse events following vaccination, mild and transient nasal or ocular discharge can be anticipated in a low percentage of horses vaccinated under field conditions. These signs typically resolve within 1 to 2 days without treatment and are sufficiently mild; owners would be unlikely to seek assistance from their veterinarian. Regardless, owners should be warned about the possible occurrence of transient nasal or ocular discharge at the time of administration of the vaccine.
JOURNAL OF EQUINE VETERINARY SCIENCE