Transfer of virus-specific antibodies from colostrum

Virus neutralizing antibodies to BVDV1, BVDV2, BoHV-1, BRSV, and PI3V transmitted through maternal colostrum protect neonatal calves against acute clinical disease during the first months of life (Ridpath et al., Reference Ridpath, Neill, Endsley and Roth2003; Patel and Didlick, Reference Patel and Didlick2004; Peters et al., Reference Peters, Thevasagayam, Wiseman and Salt2004). However, the higher the titer and longer the persistency of maternal antibodies, the higher the interference of antibody responses induced by vaccination (Munoz-Zanzi et al., Reference Munoz-Zanzi, Thurmond, Johnson and Hietala2002; Fulton et al., Reference Fulton, Briggs, Payton, Confer, Saliki, Ridpath, Burge and Duff2004); low maternally derived antibody titers generate less interference to vaccination (Ellis et al., Reference Ellis, West, Cortese, Konoby and Weigel2001; Munoz-Zanzi et al., Reference Munoz-Zanzi, Thurmond, Johnson and Hietala2002). The duration of maternal antibodies to respiratory viruses such as BVDV1, BVDV2, BoHV-1, BRSV, and PI3V depends mostly on the initial titer absorbed from maternal colostrum (Kirkpatrick et al., Reference Kirkpatrick, Fulton, Burge and Dubois2001; Munoz-Zanzi et al., Reference Munoz-Zanzi, Thurmond, Johnson and Hietala2002); however, the range of maternal antibody titers to respiratory viruses after colostrum intake is highly variable among calves (Kirkpatrick et al., Reference Kirkpatrick, Fulton, Burge and Dubois2001; Fulton et al., Reference Fulton, Briggs, Payton, Confer, Saliki, Ridpath, Burge and Duff2004; Chamorro et al., Reference Chamorro, Walz, Haines, Passler, Earleywine, Palomares, Riddell, Galik, Zhang and Givens2014). In one study the initial range of maternal antibody titers in 60-day-old calves varied from 0 to 935 for BoHV-1, 16 to 16,384 for BVDV1a, 8 to 8192 for BVDV1b, 0 to 8192 for BVDV2, and 0 to 4096 for BRSV (Fulton et al., Reference Fulton, Briggs, Payton, Confer, Saliki, Ridpath, Burge and Duff2004). In a recent study, the coefficients of variation of initial ranges of viral antibody titers derived from maternal colostrum in a group of 2-day-old calves were 28.03% for BVDV1, 37.4% for BVDV2, 24.98% for BRSV, and 43.49% for BoHV-1 (Chamorro et al., Reference Chamorro, Walz, Haines, Passler, Earleywine, Palomares, Riddell, Galik, Zhang and Givens2014).

High variation in the level of maternally derived immunity to respiratory viruses could affect the uniformity of ages at which calves become seronegative to each virus and therefore can affect responses to vaccination IFOMA. In one study, the standard deviation (SD) of the mean time to reach seronegative status to BVDV1, BVDV2, BoHV-1, BRSV, and PI3V in calves that received maternal colostrum at birth varied from 37 to 116 days (Kirkpatrick et al., Reference Kirkpatrick, Fulton, Burge and Dubois2001). Another study reported an 18–53-day variation in the mean time to reach seronegative status to the same viruses in calves that received maternal colostrum or a colostrum replacer at birth (Chamorro et al., Reference Chamorro, Walz, Haines, Passler, Earleywine, Palomares, Riddell, Galik, Zhang and Givens2014). These results indicate that differences in antibody response to vaccination IFOMA should be expected as commonly some calves will have higher and others lower antibody titers to respiratory viruses at vaccination at any time point (Kirkpatrick et al., Reference Kirkpatrick, Fulton, Burge and Dubois2001; Munoz-Zanzi et al., Reference Munoz-Zanzi, Thurmond, Johnson and Hietala2002).

Immunologic responses induced by vaccination IFOMA

A common way to evaluate response to vaccination is seroconversion (Kelling et al., Reference Kelling, Stine, Rump, Parker, Kennedy, Stone and Ross1990; Kirkpatrick et al., Reference Kirkpatrick, Step, Payton, Richards, McTague, Saliki, Confer, Cook, Ingram and Wright2008). Seroconversion is defined as a 4-fold or greater increase in serum antibody titers to a specific infectious agent and has been used to evaluate responses to vaccination in calves (Brar et al., Reference Brar, Johnson, Muscoplat, Shope and Meiske1978; Kelling et al., Reference Kelling, Stine, Rump, Parker, Kennedy, Stone and Ross1990). The absence of seroconversion following vaccination of young calves could be interpreted as vaccine failure; however, previous research demonstrated that protection against acute clinical disease caused by BVDV and BRSV can be observed in the absence of seroconversion in calves vaccinated IFOMA (van der Sluijs et al., Reference van der Sluijs, Kuhn and Makoschey2010; Stevens et al., Reference Stevens, Brown, Burdett, Bolton, Nordstrom and Chase2011). Vaccination IFOMA does not usually result in seroconversion but anamnestic antibody responses at a second dose of vaccine were reported in some studies (Brar et al., Reference Brar, Johnson, Muscoplat, Shope and Meiske1978; Menanteau-Horta et al., Reference Menanteau-Horta, Ames, Johnson and Meiske1985). Additionally, an increased persistence of maternal antibodies (reduced decay rate likely resulting from increased antibody production) and development of specific-lymphocyte proliferative responses have been reported in calves vaccinated IFOMA (Ellis et al., Reference Ellis, Hassard, Cortese and Morley1996; Fulton et al., Reference Fulton, Briggs, Payton, Confer, Saliki, Ridpath, Burge and Duff2004).

In previous studies, 28–84-day-old calves vaccinated IFOMA with MLV and KV containing BVDV1, BoHV-1, PI3V, and BRSV did not seroconvert to initial vaccination; however, at a second dose of the same vaccine given 32–112 days later, anamnestic antibody responses were observed (Menanteau-Horta et al., Reference Menanteau-Horta, Ames, Johnson and Meiske1985; Kaeberle et al., Reference Kaeberle, Sealock and Honeyman1998). In a more recent report, a low proportion of calves vaccinated with a multivalent MLV vaccine at 67 days of age seroconverted to BVDV1, BVDV2, BoHV-1, and BRSV; however, a reduced rate of decay of maternally derived antibodies and anamnestic antibody responses were observed at a second vaccination 123 days later (Kirkpatrick et al., Reference Kirkpatrick, Step, Payton, Richards, McTague, Saliki, Confer, Cook, Ingram and Wright2008). In another study, age at vaccination (15 vs. 45 days) influenced the mean time at which calves became seronegative to BVDV1 and BVDV2. Depending on the initial level of maternally derived BVDV1 and BVDV2 antibodies, vaccinated calves reached seronegative status earlier or later in life. When calves had an initial BVDV1 titer >512 or a BVDV2 titer >32, no effect of vaccination was observed; however, when BVDV1 titers were <512 and BVDV2 titers <32, vaccination increased the time at which calves became seronegative to each virus (Munoz-Zanzi et al., Reference Munoz-Zanzi, Thurmond, Johnson and Hietala2002). Another study reported a reduced rate of decay of maternal antibodies after vaccination of calves with a multivalent KV vaccine at 60 and then again at 155 days of age. The rate of seroconversion after vaccination at 60 days was minimal; however, the mean half-life of specific maternal antibodies to BVDV1, BVDV2, BoHV-1, and PI3V was increased (Fulton et al., Reference Fulton, Briggs, Payton, Confer, Saliki, Ridpath, Burge and Duff2004).

Another study reported that maternally derived antibodies to BVDV1, BRSV, BoHV-1, and PI3V decayed similarly until 140 days of age in calves vaccinated parenterally with a multivalent MLV vaccine at 2 or 70 days of age; however, calves vaccinated at 70 days of age had a higher mean BVDV1 antibody levels between 70 and 147 days after vaccination compared with calves vaccinated at 2 days of age (Woolums et al., Reference Woolums, Berghaus, Berghaus, Ellis, Pence, Saliki, Hurley, Galland, Burdett, Nordstrom and Hurley2013b). These and previous results suggest that age and level of maternal immunity at vaccination influence the induction of antibody responses in calves vaccinated IFOMA. The level of maternal antibodies that interferes with seroconversion is not uniform and varies among viral pathogens. In one study, 84-day-old calves with a BVDV1 titer of 35 seroconverted to vaccination with a MLV vaccine; however, calves with BoHV-1 titers <16 did not seroconvert (Menanteau-Horta et al., Reference Menanteau-Horta, Ames, Johnson and Meiske1985). Another study reported that calves with a BVDV1 titer between 8 and 16 seroconverted to vaccination with a multivalent MLV vaccine; however, BVDV2 titers between 4 and 8 prevented seroconversion to BVDV2 (Kirkpatrick et al., Reference Kirkpatrick, Fulton, Burge and Dubois2001). In the same study, any titer of maternal antibodies to BRSV or PI3V prevented seroconversion in vaccinated calves. Fulton et al. (Reference Fulton, Briggs, Payton, Confer, Saliki, Ridpath, Burge and Duff2004), reported that a maternal antibody titer of 128 for BVDV1a, 32 for BVDV1b, 128 for BVDV2, 32 for BRSV, and 20 for BoHV-1 interfered with seroconversion to vaccination with a multivalent KV vaccine. Downey et al. (Reference Downey, Tait, Mayes, Park, Ridpath, Garrick and Reecy2013), demonstrated that calves with a maternally derived BVDV2 antibody titer of 8.24 or higher did not seroconvert to vaccination with a MLV vaccine at 130 days of age.

Intranasal vaccination has been described as an effective way to overcome interference exerted by maternal antibodies. A recent study reported that calves vaccinated at 2–3 days of age with an intranasal multivalent MLV vaccine and a booster with the same vaccine 35 days later did not seroconvert to vaccination but had an increase in IgA specific to BVDV and BoHV-1 in nasal secretions. In the same study, cell-mediated immune responses (interferon (INF)-γ) were not detected in serum or nasal secretions of vaccinated calves (Hill et al., Reference Hill, Hunsaker, Townsend, van Drunen Littel-van den Hurk and Griebel2012). Another study reported no differences in BoHV-1-specific IgA levels in nasal secretions or cell mediated responses by peripheral blood mononuclear cells to BVDV1, BRSV, and BoHV-1 in calves vaccinated intranasally with a multivalent MLV vaccine at 2 or 70 days of age when compared with unvaccinated controls (Woolums et al., Reference Woolums, Berghaus, Berghaus, Ellis, Pence, Saliki, Hurley, Galland, Burdett, Nordstrom and Hurley2013b).

Response in calves vaccinated IFOMA and subsequently challenged with live viruses

Reduction of clinical signs of disease have been reported in calves inoculated with a virulent BVDV2 strain or vaccinated with KV and MLV vaccines containing BVDV1, BVDV2 and BRSV in the presence of maternal immunity and subsequently challenged with BVDV2 or BRSV (Ridpath et al., Reference Ridpath, Neill, Endsley and Roth2003; Patel and Didlick, Reference Patel and Didlick2004; Zimmerman et al., Reference Zimmerman, Boots, Valli and Chase2006; Woolums, Reference Woolums2007). Priming of specific T cell memory responses following vaccination has been suggested as the main source of clinical protection of BVDV2-challenged calves (Endsley et al., Reference Endsley, Roth, Ridpath and Neill2003; Platt et al., Reference Platt, Widel, Kesl and Roth2009; Stevens et al., Reference Stevens, Brown, Burdett, Bolton, Nordstrom and Chase2011). Additionally, some reports suggest that the presence of a vaccine adjuvant could aid in the induction of cell-mediated immune responses that result in clinical protection in calves vaccinated IFOMA and subsequently challenged with BVDV2 (Zimmerman et al., Reference Zimmerman, Buterbaugh, Schnackel and Chase2009; Stevens et al., Reference Stevens, Zimmerman, Butterbaugh, Barling, Scholz, Rhoades and Chase2009); Protection provided by vaccination IFOMA would ideally also prevent viremia and virus shedding, in addition to clinical disease (Thurmond et al., Reference Thurmond, Munos-Zansi and Hietala2001; Peters et al., Reference Peters, Thevasagayam, Wiseman and Salt2004). However, some studies failed to demonstrate complete clinical protection or significant reduction of viremia and nasal shedding in calves vaccinated IFOMA with different vaccines containing BVDV1, BVDV2, and BRSV and subsequently challenged with virulent BVDV2 or BRSV (Ellis et al., Reference Ellis, West, Cortese, Konoby and Weigel2001, Reference Ellis, Gow and Goji2010; Stevens et al., Reference Stevens, Brown, Burdett, Bolton, Nordstrom and Chase2011).

Failure to induce anamnestic antibody responses to vaccination and subsequent challenge with BVDV2 could result in a higher proportion of calves with viremia and nasal shedding (Stevens et al., Reference Stevens, Brown, Burdett, Bolton, Nordstrom and Chase2011); however, differences in specific humoral and cell-mediated immune responses induced by BVDV vaccines containing different biotypes (cytopathic vs. non-cytopathic) and genotypes (BVDV1 vs. BVDV2) could be expected (Lambot et al., Reference Lambot, Douart, Joris, Letesson and Pastoret1997; Palomares et al., Reference Palomares, Brock and Walz2014). Some reports suggest that while cytopathic (CP) BVDV strains commonly present in vaccines induce higher Th1-type cell mediated responses, non-cytopathic (NCP) BVDV strains commonly found in the field induce higher Th2-type humoral responses (Lambot et al., Reference Lambot, Douart, Joris, Letesson and Pastoret1997; Rhodes et al., Reference Rhodes, Cocksedge, Collins and Morrison1999). In contrast, a recent study reported that inoculation of calves with a virulent NCP BVDV2 resulted in similar expression of Th1- and Th2-type cytokines in tracheobronchial lymph nodes (Palomares et al., Reference Palomares, Brock and Walz2014). Other studies indicate that in general, higher BVDV1, BVDV2, and BRSV antibody titers in response to vaccination IFOMA result in decreased viremia and nasal shedding after BRSV and BVDV2 challenge (Vangeel et al., Reference Vangeel, Antonis, Fluess, Riegler, Peters and Harmeyer2007; Chamorro et al., Reference Chamorro, Walz, Passler, van Santen, Gard, Rodning, Riddell, Galik and Zhang2015).

Most of the experimental research has used BVDV1 and BVDV2 to evaluate protection of calves against viral challenge following vaccination IFOMA. Vaccination of 5-week-old calves with a multivalent MLV vaccine containing BVDV1 and BVDV2 and challenged 3.5 months later with BVDV2 resulted in protection against clinical disease, prevention of viremia, and reduction of leukopenia (Zimmerman et al., Reference Zimmerman, Boots, Valli and Chase2006). Another study demonstrated that calves inoculated IFOMA with live strain of BVDV2 between 2 and 5 weeks of age were protected against clinical disease at 7–9 months of at a second challenge with BVDV2 (Ridpath et al., Reference Ridpath, Neill, Endsley and Roth2003). Endsley et al. (Reference Endsley, Roth, Ridpath and Neill2003), reported that calves exposed to a live strain of BVDV2 at 2–5 weeks of age develop BVDV2-specific CD4, CD8, and γ/δ T cells and anamnestic antibody responses at challenge with BVDV2. In the same study, calves vaccinated at 7 weeks of age with a KV or multivalent MLV vaccine containing BVDV1 and BVDV2 developed anamnestic antibody responses to BVDV2 at second vaccination at 14 weeks of age; however, in this study the KV vaccine failed to induce T-cell responses specific to in vaccinated calves.

Although the studies described above showed that vaccination IFOMA can protect calves against clinical disease following BVDV2 challenge, the practice is not always effective. Failure to provide clinical protection and reduction of viremia has also been reported in calves vaccinated IFOMA. In one study, 10–14 day-old calves vaccinated with a MLV vaccine containing BVDV1 were not protected at challenge with BVDV2, 4.5 months after vaccination. Sixty six percent of vaccinated calves in this study had to be euthanized due to severity of clinical disease (Ellis et al., Reference Ellis, West, Cortese, Konoby and Weigel2001). In the same study, 10–14 day-old calves deprived from passive immunity to BVDV1 and BVDV2 and also vaccinated, seroconverted to vaccination, had less viremia, and were protected against challenge. Another study demonstrated that vaccination of calves at 3 days of age with a multivalent non-adjuvanted MLV vaccine containing BVDV1 and BVDV2 resulted in clinical protection and reduction of mortality at 7–9 months of age when calves were challenged with BVDV2; however, in this study 80% of calves vaccinated IFOMA became viremic after challenge (Stevens et al., Reference Stevens, Brown, Burdett, Bolton, Nordstrom and Chase2011). A more recent study reported that calves from 1 to 2, 4 to 5, and 7 to 8 weeks of age vaccinated IFOMA, with a multivalent MLV vaccine containing BVDV1 and BVDV2, developed BVDV1- and BVDV2-specific T-cell-mediated responses and were clinically protected after challenge with BVDV2 at 12 weeks after vaccination; however, only calves vaccinated at 4–5 and 7–8 weeks developed anamnestic antibody responses to BVDV1 and BVDV2 after challenge. Cell-mediated responses to BRSV, BoHV-1, or PI3V after vaccination were not detected in any of the calves (Platt et al., Reference Platt, Widel, Kesl and Roth2009).

Protection against challenge with BRSV in calves vaccinated (parenterally or intranasally) IFOMA has also been reported. In one study, 2-week-old calves vaccinated parenterally at 2 and 6 weeks with a KV BRSV vaccine demonstrated significantly less signs of disease and reduced viral shedding after challenge at 10 weeks of age. Although anamnestic antibody responses were not observed, vaccinated calves demonstrated a slower rate of decay of maternal BRSV antibodies compared with controls (Patel et al., Reference Patel and Didlick2004). When a third dose of the same vaccine was given at 18 weeks of age, anamnestic antibody responses were induced. Another study reported that 2-week-old calves vaccinated parenterally with a KV BRSV vaccine and challenged 21 days later did not develop anamnestic antibody responses; however, vaccinated calves were protected against severe clinical disease and had increased BRSV-specific IFN-γ production in peripheral lymphocytes 1 week after challenge (van der Sluijs et al., Reference van der Sluijs, Kuhn and Makoschey2010).

Intranasal (IN) vaccination of calves with MLV vaccines containing BRSV has produced mixed results. Woolums et al. (Reference Woolums, Brown, Brown, Cole, Scott, Williams and Miao2004), reported that 4 to 6-week-old calves vaccinated IFOMA with an IN MLV vaccine and challenged at 8 weeks of age with BRSV had reduced clinical signs of disease following challenge. In this study, anamnestic antibody responses were not induced in vaccinated calves; however, IFN-γ production was increased in lymphocytes from lymphoid bronchial tissue. Another study reported that 3 to 8-day-old calves vaccinated IN with a MLV BRSV vaccine were not completely protected against challenge with BRSV at 4.5 months of age (Ellis et al., Reference Ellis, Gow and Goji2010). In this study, vaccinated calves demonstrated similar levels of virus shedding and similar lung lesions compared with controls. Additionally, antibody responses in serum and nasal secretions were not different between vaccinated and unvaccinated calves. Intranasal or subcutaneous (SC) vaccination of 3 to 8-day-old BRSV-seronegative calves challenged with BRSV 21 days after vaccination resulted in clinical protection; however, significant antibody responses or production of IgA in the upper respiratory tract were not detected after challenge (Ellis et al., Reference Ellis, Gow and Goji2010). In a similar study 2 to 9-week-old calves were vaccinated with a single component IN MLV BRSV vaccine, calves were protected at challenge 8 days after vaccination and had increased concentrations of IgA and IFN-α in nasal secretions. Additionally, vaccinated calves developed anamnestic antibody responses following BRSV challenge when a 2 dose of vaccine was administered 21 days later (Ellis et al., Reference Ellis, Gow, West, Waldner, Rhodes, Mutwiri and Rosenberg2007).

Field trials of vaccination IFOMA and prevention of bovine respiratory disease

The best way to evaluate the efficacy of vaccination of calves IFOMA against natural infection with respiratory viruses is through well-designed field trials. Unfortunately, the inability to control the occurrence of natural disease and other logistic complications under field conditions limit publication of these types of studies. A previous study described the efficacy of vaccination of calves at 3 and 5 weeks of age with a MLV BRSV vaccine and a Mannheimia haemolytica leucoctoxin/Histophilus somni bacterial extract to reduce a high incidence of BRDC in calves from a farm where BRSV and M. haemolytica had been previously isolated. The proportion of calves treated for BRDC as determined by the owner was higher in calves that did not receive any vaccine (34%) compared with calves that received both vaccines (15%) (Van Donkersgoed et al., Reference Van Donkersgoed, Potter, Mollison and Harland1994). In another study on a dairy heifer rearing operation, calves were vaccinated IFOMA at 15 days of age with a multivalent KV vaccine containing BVDV1 and at 45 days of age with a multivalent MLV vaccine containing BVDV1. Exposure to BVDV measured as proportion of calves that seroconverted to BVDV1 was reduced in vaccinated calves. Additionally, it was estimated that vaccination prevented 48% of BVDV1 transmission among calves from 4 to 9 months of age (Thurmond et al., Reference Thurmond, Munos-Zansi and Hietala2001). A recent trial involving 2874 dairy calves reported that vaccination of calves with a multivalent MLV vaccine containing BVDV1, BVDV2, and BRSV at 21 days, 28 days, or both did not reduce incidence of BRDC during the first 3 months of life (Windeyer et al., Reference Windeyer, Leslie, Godden, Hodgins, Lissemore and LeBlanc2012); however, the median calf age for BRDC treatment was 30 days and 44% of the cases of BRDC occurred before completion of the vaccination protocol.

Clinical recommendations based on current research

Experimental trials evaluating the efficacy of vaccination IFOMA against common respiratory viruses in young calves indicate that immunological responses and clinical outcome following vaccination are variable and could be influenced by several factors. However, research evaluating the response of calves vaccinated prior to experimental challenge with BVDV2 or BRSV provides the basis for some clinical recommendations that may be helpful in planning vaccination programs for young calves:

• • A single dose of a multivalent MLV vaccine containing BVDV1, BVDV2 and/or BRSV administered parenterally or intranasally to calves that received maternal colostrum and are older than 2 weeks can offer some degree of clinical protection against challenge by these viruses later in life when maternal antibodies have disappeared.

• • A single dose of a KV vaccine containing BVDV1, BVDV2 and/or BRSV administered parenterally to calves that received maternal colostrum and are older than 2 weeks could offer clinical protection after challenge; however, the administration of a second dose after 4 weeks is recommended.

• • Parenteral or intranasal administration of KV or MLV vaccines containing BVDV1, BVDV2, and/or BRSV to calves younger than 2 weeks with high levels of maternally derived antibodies may not be useful, as vaccination might not result in clinical protection after challenge later in life.

• • Parenteral or intranasal administration of MLV vaccines containing BVDV1, BVDV2, and/or BRSV to calves deprived of specific maternal immunity due to failure to receive an adequate volume of good quality colostrum effectively primes B- and T-cell responses and can offer clinical protection to calves after challenge.