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December 8, 2010

VETERINARY SERVICES MEMORANDUM NO. 800.209

TO: VS Management Team (VMST)

Directors, Center for Veterinary Biologics

Biologics Licensees, Permittees, and Applicants

FROM: John R. Clifford /s/ Jere L. Dick, for

Deputy Administrator

Veterinary Services

SUBJECT: Bovine Corona Virus and Rotavirus Master Reference Qualification by 

Colostral Antibody Titers

I. PURPOSE

The purpose of this memorandum is to inform interested parties that the Center for 

Veterinary Biologics (CVB) will allow the qualification of Master References used for 

serial release of vaccines containing inactivated bovine corona virus (BCV) and bovine 

rotavirus (BRV) based on agent-specific colostrum antibody titer, if there is a wellcharacterized relationship between the colostrum antibody titer and efficacy by passive 

immunity in neonatal calves. 

II. BACKGROUND

In vitro relative potency tests rely on the use of a Master Reference whose potency has 

been related to efficacy. Studies to qualify (reference qualification) or requalify 

(reference requalification) Master References have typically been conducted as 

vaccination-challenge studies in the target species. Vaccines containing BCV and BRV 

antigens that utilize an in vitro potency test for serial release have required vaccinationchallenge studies for each pathogen. These studies are conducted in three stages: 

(1) vaccination of pregnant cattle, (2) feeding neonatal calves the colostrum, followed by 

(3) challenge of neonatal calves with one of the pathogens. At times, this challenge 

model system may not closely mimic field conditions, because the pathogenesis of 

neonatal diarrhea typically involves more than a single pathogen. Such studies are also 

complicated by the scarcity of adult cattle that are naïve to BCV and BRV. 

Consequently, study results utilizing experimental challenge models can be difficult to 

reproduce. 

BCV and BRV vaccines are used to vaccinate cattle in order to improve the colostrumderived immunity of neonatal calves nursing vaccinated cattle compared to those nursing 

United States

Department of

Agriculture

Animal and Plant

Health Inspection

Service

Veterinary Services

Washington, DC

20250
VETERINARY SERVICES MEMORANDUM NO. 800.209

Page 2

unvaccinated cattle. The protective mechanism is due, in part, to the high level of 

antibodies in colostrum directed against the disease-causing agents. A potential correlate 

of vaccine efficacy and, consequently, potency is the level of antibodies found in the 

colostrum of the vaccinated dams. It is reasonable that a particular level of agent-specific 

antibody in colostrum is associated with adequate protection in neonatal calves.

III. ACTION

A. Titer-Response Relationship - The CVB will consider proposals to qualify/

requalify BCV and BRV Master References by colostral antibody titer, provided 

there is a functional titer-response relationship between the agent-specific 

colostrum titer and the pathogen-specific response to challenge. A functional 

titer-response relationship means that the probability of the response can be 

predicted from the colostral titer with reasonable precision.

B. Study Design - The titer-response relationship must be estimated from studies 

designed for that purpose and specify the primary outcome either with a case 

definition that categorizes calves as affected or unaffected by challenge or with 

an explicit measure of disease severity. The antibody titers of the colostrums 

must span a range from a level associated with low efficacy to a level associated 

with high efficacy. This may require experimental formulation of colostrum 

mixtures with known antibody content. To do so, colostrum from vaccinated 

cattle may be diluted with colostrum from nonvaccinated cattle.

C. Required Titer - If there is a functional titer-response relationship, and the titers 

and response span a suitable range, a statistical model of the functional 

relationship can be estimated. The model may then be used to predict the 

response probability associated with any particular antibody titer. The required 

titer is that for which the expected probability of a vaccinated calf being 

unaffected by challenge is 80% (ED80). The ED80 must be estimated with 

enough precision so that its confidence interval is no wider than 35%.

D. Master Reference Qualification or Requalification - Conduct a study with a 

minimum of 20 vaccinated animals. Include a sentinel group of five animals to 

monitor exposure during the study. Cattle used in the vaccination-challenge 

studies are not required to be seronegative for BCV and BRV. In studies to 

qualify or requalify references based on colostral antibody levels, the animals 

should have a serostatus similar to those used in the vaccination-challenge 

studies that established the titer-response relationship.

1. BRV - A BRV Master Reference may be qualified or requalified if at least 

80% of the vaccinated cattle have a colostral antibody titer that meets or 

exceeds the ED80.
VETERINARY SERVICES MEMORANDUM NO. 800.209

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2. BCV - It is often difficult to isolate the role of the BCV-specific titerresponse relationship from protection afforded by other antigens present in 

the vaccine complicating the estimation of the BCV titer-response 

relationship.

If the BRV titer-response relationship has been well characterized, and a high 

level of protection against BCV challenge has been demonstrated in 

passively immunized calves, the CVB will consider requests for reference 

qualification by colostral titer for BCV also. If approved, the BCV ED80 will 

be the 80th percentile of the distribution of the BCV colostral antibody titers 

observed in the pivotal efficacy studies. 

E. Antibody Titration Assay - The test method used to titer or quantify the antibody 

level in colostrum must be validated as per Veterinary Services Memorandum 

800.112.

IV. SCOPE AND IMPLEMENTATION

This policy is effective immediately for BRV and BCV antigens as an alternative to 

target animal challenge and may be applied to currently licensed products, those in the 

prelicense stage, and future products.