Vaccination to stop transmission Arjan Stegeman j.a.stegeman@uu.nl Faculty of Veterinary Medicine
Goals of vaccination To prevent clinical disease (production, animal welfare, treatment costs, antimicrobial usage) To eliminate infection or prevent transmission upon introduction Examples: Avian Influenza and
For elimination vaccination should not only induce clinical protection, but also stop virus transmission
H5N1 was not controlled in the countries where vaccination has been applied New episode of outbreaks in Africa 2015 China, Vietnam, Egypt and Indonesia have been infected ever since!
Vaccination to stop transmission Introduction to transmission and how it determines the aim of vaccination How can transmission be measured Homogeneity of immune response upon vaccination Avian Influenza and Newcastle Disease used as examples
Measure of transmission R 0, Basic Reproduction ratio : average number of secondary infections caused by one infected animal in a fully susceptible population R 0 = 2
Measure of transmission R 0, Basic Reproduction ratio : average number of secondary infections caused by one infected animal in a fully susceptible population HPAI R 0 = 2 10 (Tiensin 2007; Bos 2009; Stegeman, 2015) LPAI R 0 = 4 15 (Van der Goot 2004; Gonzales, Saenz) ND R 0 > 4 (Van Boven, 2008)
R 0, Basic Reproduction ratio Determined by : 1) Susceptibility to infection (infectious dose) 2) Infectivity upon infection (excretion of pathogen) 3) Contact structure between animals
Transmission in a flock As the transmission progresses in a flock the effective Reproduction ratio R E, decreases because of the decreasing proportion of susceptible birds
Transmission in a flock Transmission stops when : R E < 1 At that point each infected bird infects less than 1 other bird so infection will fade out
Transmission in a flock At R E < 1 usually not all birds have been infected. The proportion of susceptible birds at that point equals 1-1/R 0. These birds are protected by Herd Immunity (surrounded by immune birds)
Vaccination to stop transmission in a population Effectiveness of a vaccine (how good is it in blocking transmission) Vaccination coverage (proportion vaccinated)
Vaccination to stop transmission In case a vaccine can prevent infection or excretion upon infection completely Herd Immunity is sufficient if the proportion of vaccinated birds exceeds 1 1/R 0 HPAI : 50% - 90% LPAI : 75% - 93% ND : > 75 %
What if the vaccine cannot prevent infection or excretion upon infection completely? Measure transmission among vaccinated birds! To prevent massive transmission in a flock a vaccinated but infected bird needs to infect on average less than one other (vaccinated) bird R v < 1
Transmission Experimental set-up experiments 5 inoculated birds are placed in an isolator with 5 contact animals the infection chain is monitored by taking swabs from the trachea and cloaca swabs are subjected to virus isolation and/or PCR At least two replicate experiments comparing vaccination and control
Susceptible Transmission experiment, HPAI H7N7 (van der Goot, 2005) Vaccinated d0 Non-vaccinated d0
Infectious Transmission experiment, HPAI H7N7 infected and non-infected chickens are mixed Vaccinated d1 Non-vaccinated d1
PCR results challenge d14 after vaccination D 1 D 2 D 3 D 4 D 5 D 6 D 7 D 8 D 9 D 10 D 14 I +/- -/+ +/+ -/+ -/+ -/+ -/+ -/+ -/+ -/+ nd/- Inoculated I +/+ +/+ +/+ +/+ -/+ -/+ -/+ -/+ -/+ -/+ nd/- H7N1 I +/- +/- +/- +/+ -/+ -/+ -/+ -/+ -/+ -/- nd/- Vaccinated I +/- +/+ -/+ -/+ -/- -/+ -/- -/+ -/- -/- nd/- I +/- -/- -/+ -/+ -/+ -/- -/- -/- -/- -/- nd/- S nd -/- -/- -/- -/- -/- -/- -/- -/- -/- nd/- Contact S nd -/- -/- -/- -/- -/- -/- -/- -/- -/- nd/- H7N1 S nd -/- -/- -/- -/- -/- -/- -/- -/- -/- nd/- Vaccinated S nd -/- -/- -/- -/- -/- -/- -/- -/- -/- nd/- S nd -/+ -/- -/- -/- -/- -/- -/- -/- -/- nd/- I +/- +/- -/+ -/- -/- -/+ -/- -/- -/- -/- nd/- Inoculated I -/- -/- -/- -/- -/- -/- -/- -/- -/- -/- nd/- H7N1 I +/+ +/+ +/+ +/+ -/+ -/+ -/+ -/- -/+ -/- nd/- Vaccinated I +/- -/- -/- -/- -/- -/- -/- -/- -/- -/- nd/- I +/+ +/- +/+ +/+ -/+ -/+ -/- -/- -/- -/+ nd/- S nd -/- -/- -/- -/- -/- -/- -/- -/- -/- nd/- Contact S nd -/- -/- -/- -/- -/- -/- -/- -/- -/- nd/- H7N1 S nd -/- -/- -/- -/- -/- -/- -/- -/- -/- nd/- Vaccinated S nd -/- -/- -/- -/- -/- -/- -/- -/- -/- nd/- S nd -/- -/- -/- -/- -/- -/- -/- -/- -/- nd/-
PCR results unvaccinated controls Results: unvaccinated chickens D 1 D 2 D 3 D 4 D 5 D 6 D 7 D 8 D 9 D 10 D 14 D 16 D 21 I +/+ +/+ I +/+ +/+ +/+ Inoculated I +/+ +/+ +/+ I +/+ +/+ +/+ +/+ I +/+ +/+ +/+ S nd +/- +/- +/+ +/+ S nd -/- +/- +/+ +/+ +/+ Contact S nd +/- +/- +/+ +/+ +/+ +/+ +/+ +/+ -/+ -/- -/- -/- S nd -/- +/- +/+ +/+ +/+ S nd +/- +/- +/- +/+ +/+ +/+ +/+ -/+ -/+ -/+ -/+ -/- I +/+ +/+ +/+ +/+ I +/- +/+ +/+ +/+ Inoculated I +/+ +/+ +/+ +/+ I +/- +/+ +/+ +/+ I +/+ +/+ +/+ +/+ +/+ S nd -/- +/+ +/+ +/+ +/+ S nd -/- +/- +/+ +/+ +/+ Contact S nd -/- +/- +/+ +/+ +/+ S nd -/- +/- +/+ +/+ +/+ S nd -/- +/- +/- +/+ +/+ +/+ +/+ +/+ +/+ -/+ -/+ -/-
Recovered Dead Vaccination - Transmission experiment, HPAI H7N7 Vaccinated d21 Non-vaccinated d21
Model pig
Results 1. final size analysis final size R (95% CI) H 0 :R 1 H 0 :R vacc =R unvacc unvaccinated 5,5 (1.3- ) 1 H7N1 (7 days) 0,1 0.2 (0-1.1) 0.04 <0.001 H7N3 (7 days) 1,5 1.4 (0.4-2.9) 0.78 0.1 H7Nx (14 days) 0,0 0 (0-0.9) 0.02 <0.001
Golden Pheasant
Experiments to assess vaccine induced reduction of transmission To investigate effect on susceptibility and infectivity (pairwise) To investigate effect on indirect transmission
Experimentally quantify transmission in groups of vaccinated birds (R 0 <1?) In experiments vaccination stopped (R v <1) the transmission of HPAI infections among chickens, teals, ducks and turkeys, but not in pheasants (van der Goot et al.; Bouma et al., Bos et al., etc). Birds vaccinated under field conditions seem to behave differently. Why?
Vaccination in the Field Vaccination of SPF chickens against AI under experimental conditions usually results in high (>4) and quite homogeneous HI titers. Titers of commercial chickens vaccinated in the field are often much lower and more variable (Koch, Poetri)
Faculty of Veterinary Medicine
Vaccination in the Field (Poetri et al., 2011, 2014) Type Vaccination Challenge R v Broiler MDA d1 1.0 (0.45-2.1) Broiler MDA d28 5.1 (3.0-8.4) Broiler d1 d28 5.5 (3.1-9.3) Broiler d10 d28 4.4 (2.3-8.3) Layer* d28 d56 3.1 (1.9-4.8) * Birds paired based on HI titers, titers were generally low and varied from negative 5log2, no clinical signs observed and measurable virus excretion was limited
Vaccination against ND (Van Boven et al., 2008) Vaccine Virus R v -low titer R v -high titer La Sota NL93 3.4 (1.5-8.4) 1.1 (0.46-1.7) La Sota Herts33/56 0.95 (0.27-2.8) 0.19 (0.02-0.79) La Sota Calif. 71 > 1.8 0.38 (0.04-0.98) Ulster NL93 > 2.1 1.5 (0.50-3.9) 3.1 (1.8-4.3) 0.72 (0.41-1.0) Broilers were spray vaccinated at day 1 and received a second vaccination by atomist around d14. Low titers : 0 2log2 High titers: 3log2
Vaccination to stop transmission In case a vaccine cannot completely prevent infection or excretion upon infection, but R v- high <1, Herd Immunity is sufficient if : R E = pr v-high + (1 p)r v-low <1 In the ND example this means that at least 88% (58%-100%) of the birds in the flock needs to have a high immunity (titer 3log2) p = proportion birds with high immunity
Summary (1) To eliminate infection vaccines need reduce transmission to level where R E < 1 If vaccination completely prevents infection and/or blocks excretion the proportion vaccinated birds in a flock needs to be at least 1-1/R 0 For imperfect vaccines the effect of vaccination on transmission can be quantified experimentally
Summary (2) To eliminate infection an imperfect vaccine should reduce susceptibility and/or pathogen excretion to a level where R v < 1 Immunity induced by vaccination under field conditions is often lower than that induced under experimental conditions. Heterogeneity in immune response and its effect on Herd Immunity should be taken into account