Environmental Assessment – Rift Valley Fever Vaccine, Modified Live Virus (Unlicensed in Canada and USA)

For Public Release

February 1, 2013

Prepared and revised by the Canadian Centre for Veterinary Biologics (CCVB) of the Canadian Food Inspection Agency (CFIA), this environmental assessment includes information that was current at the time of its preparation. It is possible, however, that the situation may have changed since that time. Please consult CCVB, if you have any questions.

1. Introduction

1.1 Objective of the Proposed Action

Pfizer Animal Health Canada Inc. has submitted the following vaccine for licensing in Canada and the U.S.:
Rift Valley Fever Vaccine, Modified Live Virus (Unlicensed in Canada and the U.S.).

Rift Valley Fever (RVF) has never been found in Canada. This disease falls under the category of reportable diseases, according to the Health of Animals Act. The CFIA is responsible for prevention, control, and eradication of this disease in Canada. The disease is a potential threat to Canada due to increased travel and trade. The CCVB of the CFIA is responsible for licensing veterinary biologics for use in Canada. Conditional licensure of this vaccine is being considered to provide the CFIA with an additional tool to control this disease if an outbreak were to occur in Canada. The vaccine will not be available for general sale in Canada, following completion of requirements for conditional licensing. The company must conduct a field safety study as part of the requirements for licensing this vaccine. Data from this field safety study will also be reviewed by the U.S. Department of Agriculture (USDA) – Centre for Veterinary Biologics (CVB) as part of licensing this product in the U.S. The CCVB prepared this environmental assessment to evaluate the feasibility of conducting the field safety study in Canada and to be part of the overall assessment for licensing the vaccine. This document contains information on the vaccine, animal safety, human safety, proposed field safety study, and other environmental considerations regarding its use in Canada. The document is based on published literature and several unpublished study reports, submitted by Pfizer Animal Health Canada Inc. in support of licensing of this product.

1.2 Background – Information on Problem and Action

RVF virus is an insect-borne pathogen that causes disease in cattle and other domestic livestock. A member of the phlebovirus family, RVF virus contains an RNA genome composed of three (small, medium, and large) segments. RVF virulence is described in detail by Swanepoel and Coetzer in a chapter from Infectious Diseases of Livestock with Special Reference to Southern Africa vol. 1. Briefly, RVF is an acute disease of domestic livestock in Africa and Madagascar. It is mosquito borne, characterized by necrotic hepatitis and a hemorrhagic state. Often, symptoms are mild or subclinical. The disease is most severe in sheep, cattle, and goats, producing high abortion rates in pregnant animals and high mortality in newborn animals. RVF can also infect humans and usually results in mild to moderate flu-like symptoms. A small percentage of infected humans have severe complications, including ocular lesions, encephalitis, and hemorrhagic disease.

Pfizer Animal Health Inc. (now known as Zoetis Inc.) has developed a modified live Rift Valley Fever vaccine, based on an attenuated strain. The company has applied for licensure of this vaccine in the U.S. and Canada for use by the USDA-National Veterinary Stockpile (NVS) and by the CFIA in an emergency situation.

1.3 Proposed Study – Field Safety of a Rift Valley Fever Vaccine

Pfizer Animal Health Canada Inc. has proposed to conduct a field safety study, to demonstrate the field use safety of the Rift Valley Fever Modified Live Virus Vaccine, when administered to cattle, including young calves (three months of age), under typical field use conditions, as a requirement for conditional licensing of this vaccine in the U.S. and Canada.

The company submitted a study protocol for this field safety study, which was reviewed and approved by the CCVB. The proposed field safety study will be conducted at a commercial feedlot in Canada.

2. Purpose and Need for RVF Vaccine Development

2.1 Significance

Rift Valley Fever Vaccine, Modified Live Virus (Unlicensed in Canada and the U.S.) is a vaccine being developed to help control RVF, a mosquito-borne zoonotic disease that is currently exotic to the U.S. and Canada, but is on the U.S. Department of Homeland Security's (DHS) Select Agent list. It is anticipated that a vaccine supply will be maintained as part of the USDA stockpile for use if a RVF outbreak were to occur in the U.S. or Canada. For other markets, in countries or regions where RVF is endemic or that experience outbreaks of the disease, the vaccine may be sold or distributed under a "For Export" or USDA Product License.

2.2 Rationale

The USDA-CVB requires safety studies, conducted under field use conditions, in host animals as part of the product licensure process to detect the types of adverse events that may occur only under field use conditions. CFIA-CCVB has also agreed to participate in this vaccine review. The field safety study, supporting the licence of this vaccine, will evaluate a total of 600 head of cattle, with half the animals tested in the U.S., and the other half in Canada.

3. Alternatives

3.1 Available Choices and Their Relative Scientific Merits

In addition to the attenuated vaccine strain, Clone 13 and Smithburn are additional RVF vaccine strains that are licensed for use in Africa and that may be under evaluation in other countries, with clone 13 being the one quoted most often (von Teichman, et al., 2011).

The 2011 Kortekaas and colleagues'conference proceedings state that, historically, two vaccines have been available for control of RVF virus in livestock. The first is based on the live attenuated Smithburn virus. Although this vaccine is inexpensive and provides lasting immunity after one dose, its residual virulence renders it unsuitable for application in newborn and gestating livestock. A safe alternative is based on inactivated whole virus. For optimal immunity, however, this vaccine requires a booster and annual revaccination. Drawbacks of these classical vaccines explain the need for a new generation of RVF virus vaccines.

Workshop participants agreed that novel vaccines should be cost-effective and provide swift and long duration of immunity after a single vaccination and that application should be safe, regardless of the physiologic state of the animal. The possibility of needle-free delivery would be advantageous, especially when absence of virus circulation cannot be definitely established, and reuse of needles represents a risk for further dissemination. Novel vaccines that enable differentiation between infected and vaccinated animals (DIVA) by use of an appropriate discriminatory assay would be beneficial.

The live attenuated candidate vaccines that were discussed during the meeting were the MP-12 vaccine, a recombinant RVF virus that contains deletions in 2 of the 3 genome segments, and the clone 13 vaccine. The vaccine data presented during the workshop suggest that all 3 live attenuated vaccine candidates are highly immunogenic and safe in ewes during the first trimester of gestation and that the MP-12 vaccine is immunogenic and a candidate for human vaccination. The clone 13 vaccine was recently registered and marketed in South Africa; the other live-attenuated vaccines could also come to market in the next decade. ELISAs, based on non-structural proteins, could be used as DIVA assays to accompany these vaccines.

3.2 Selection Criteria and Justification

As the strain used to prepare this vaccine is the only strain currently excluded from the U.S. Select Agent requirements, it is the strain of choice for initial development of the RVF vaccine, and was specified by the U.S. Department of Homeland Security in its request for proposal for licensing. Field safety studies in the host animal are specifically required prior to licensure. The number of animals and the location of field studies in the U.S. and Canada were negotiated with CVB and CCVB reviewers.

4. Molecular and Biological Characteristics of Parental and Recombinant Organisms

4.1 Identification, sources, and strains of parental organisms

The parental RVF strain for the attenuated vaccine was initially obtained by Caplen and colleagues in 1985. CCVB reviewed the details of its further propagation, purity, and genetic characterization.

4.2 Source, Description, and Function of Foreign Genetic Material

The vaccine is prepared from an attenuated strain. Hence, this vaccine is not biotechnology-derived and is considered a modified live virus conventional vaccine.

4.3 Method of Accomplishing Genetic Modification

The vaccine strain has no genetic modification. The process of attenuation of the virus and preparation of master seeds were reviewed by CCVB. The RVF master seed virus (MSV) was established by the United States Army Medical Research Institute of Infectious Diseases (USAMRIID). Pfizer obtained the virus as a frozen stock, using to establish the MSV, which was satisfactorily tested in the Pfizer Biological Control Laboratory in accordance with 9CFR and EU standard requirements. The MSV was also tested by the USDA-CVB and confirmed as satisfactory on May 27, 2011. The master cell stock was also tested by the CVB and confirmed as satisfactory on May 26, 2011.

4.4 Genetic and Phenotypic Stability of Vaccine Organism

4.4.1 Genetic stability

Not applicable. This vaccine is not biotechnology-derived. This is an attenuated vaccine and does not contain any foreign genetic material. Genetic stability of the vaccine strain was evaluated in serial passage studies. Minor deletions of the viral genome were detected in virus recovered after serial passage. The deletions that were observed have been previously observed by workers at USAMRIID and are associated with decreased virulence (Pfizer Study Report).

4.4.2 Phenotypic stability

Titers obtained in tissue culture with original seed obtained from USAMRIID and Pfizer's MSV were essentially identical. A virus-specific monoclonal antibody was used to identify the original isolate and Pfizer's MSV. Phenotypic stability of the Pfizer vaccine strain was evaluated in serial passage studies (Pfizer Study Reports). No phenotypic changes were identified, although genetic changes (deletions), as mentioned above, were observed.

4.5 Potential for Recombination and Horizontal Gene Transfer

Unknown. For this vaccine strain, none has been detected in any published study or in any of the studies conducted at Pfizer or USAMRIID or by collaborators at the University of Texas.

4.6 Host Range: Specificity, Tissue Tropism, and Shed/Spread Capabilities

4.6.1 Wild type Host range specificity

Livestock:

  • sheep: ~20%–30% mortality, abortion
  • cattle: ~10%–15% mortality, abortion
  • goats: ~5%–10% mortality, abortion
  • camels: survive, low viremia, abortion
  • water buffalo: survive, low viremia
  • African buffalo: survive, abortion
  • other African ungulates: antibody only

Human Infection:

  • current developing outbreak in Kenya: >150 human deaths reported
  • previous infection of a Canadian tourist documented
  • established epidemics in new territory: Egypt, Saudi, Yemen

Tissue Tropism in susceptible host(s):

Tissue tropism of RVF is described in detail in the Swanepoel and Coetzer chapter. Briefly, wild-type RVF in vivo spreads to critical organs such as the spleen, liver, and brain. Immunofluorescence and titration studies suggest lymph nodes, liver, and spleen as major sites of viral replication. High levels of virus can be isolated from the serum of infected animals.

4.6.2 Vaccine strain Host Range specificity

Livestock:

  • sheep: no observed mortality, no observed abortion, protective immunity develops
  • cattle: no observed mortality, one report of abortion in first trimester of an animal, result not repeated, no abortions observed in second or third trimester pregnant animals, protective immunity develops.
  • no other species known to have been tested

Laboratory Animals:

  • mice: vaccine decreased in virulence, but fatal in approximately 4% of vaccinated animals, with encephalitis observed 10 to 12 days post-vaccination, no known studies on abortion in pregnant mice, protective immunity develops in surviving mice (Pfizer Study Report)
  • hamsters: vaccine decreased in virulence, but was fatal in a small number of hamsters (Rossi and Turrell 1988)
  • rhesus monkeys: low transient neurovirulence (Morrill and Peters, 2003).

Human Infection:

No observed mortality or clinical signs of viremia post-vaccination, not known to have been tested in pregnant humans, protective immunity develops

Shed/spread capabilities:

A study with minimum immunizing dose (MID) was performed at Pfizer at several virus input levels. For each group, two sentinel animals were commingled with the vaccinates. While all vaccinated animals seroconverted to the vaccine virus, none of the sentinel animals seroconverted, indicating no vaccine virus spread to susceptible animals. In this study, no virus was isolated from any vaccinated or control animals in serum, nasal, or fecal samples. In a one-year Duration of Immunity study, no control animal ever seroconverted, despite commingling with seropositive vaccinates (Pfizer Study Reports).

Tissue Tropism

The Summary Report from Pfizer's pilot study demonstrated that the recovery of the vaccine virus from blood was variable, even in very young animals (7 positives out of 60 samples), but recovery from liver homogenates was more reliable (8 positive out of 8 samples) during the first few days post-vaccination, leading to the selection of liver as the target tissue and Day 4 for the collection of samples in the pivotal reversion to virulence cattle study. These observations were consistent with results from previous studies conducted on the vaccine virus.

4.7 Route of Administration/Transmission

The administration route of the vaccine is subcutaneous as a single dose. The vaccine will be injected in young calves (age three months or over) and heifers in the proposed field safety study. The label of the vaccine will state, "For vaccination of healthy cattle, 3 months of age or older as an aid in the prevention of disease associated with Rift Valley Fever infection."

5. Human Safety

5.1 Previous Safe Use

The RVF vaccine virus strain was originally developed for use in humans by the USAMRIID at Fort Dietrich Maryland. The vaccine has been tested in humans (U.S. soldiers and scientists) and has been found to be safe. No adverse events have been observed in the limited human clinical trials to date. Safety of the RVF vaccine strain has not been established for immunosuppressed individuals, pregnant women, and children.

5.2 Probability of Human Exposure

Spread and shed of the vaccine has not been observed. It is unlikely that humans could be exposed to RVF vaccine strain during the proposed field safety study. There must be efforts to avoid accidental exposure to the vaccine strain, particularly in pregnant women, immunosuppressed humans, or children for whom safety has not been demonstrated.

Experimentally, vaccine virus can be transmitted by mosquitoes after oral pledget feeding or inoculation (Turrell & Rossi, 1991). However, because of the very low viremia following vaccination (Peters CJ, unpublished), it is unlikely mosquitoes would become infected upon feeding on a vaccinated animal.

To avoid any potential contact of mosquitoes and other vectors with the vaccinated animals, it is emphasized that the proposed field safety study be completed and that animals used in the study are disposed of well before the beginning of vector season in Canada.

5.3 Possible Outcomes of Human Exposures

Based upon previous safe use of the RVF vaccine strain in U.S. soldiers and scientists, potential human exposure to the vaccine virus is not expected to be a significant health concern.

5.4 Pathogenicity of Parent Micro-Organisms in Humans

The parent virus of the vaccine strain induced an uncomplicated human febrile case in Egypt. In general, RVF virus can infect humans and usually results in mild to moderate flu-like symptoms. A small percentage of infected humans have severe complications, including ocular lesions, encephalitis, and hemorrhagic disease.

5.5 Effect of Gene Manipulation on Pathogenicity in Humans

The RVF vaccine strain is attenuated and is not virulent for humans. Previous use of the vaccine in humans did not demonstrate any adverse events. (Refer to section V.A.) The attenuation has led to a decrease in pathogenicity in humans.

5.6 Risk Associated with Widespread Use of the Vaccine

Widespread use of the vaccine is not proposed at this stage. Thus far, studies have shown that RVF vaccine strain produces very mild transient viremia in vaccinated animals. It is unlikely that mosquitoes would become infected by feeding on the vaccinated animals or have the ability to transmit the infection to a susceptible population. There is no evidence of reversion to virulence of the RVF vaccine strain following inoculation in calves and lambs.

To further eliminate the chances of spread of the vaccine virus, the proposed field safety study will be conducted in the non-vector season, and the animals used in the study will be disposed of soon after completing the study.

6. Animal Safety

6.1 Previous Safe Use

The RVF vaccine strain presents low neurovirulence in rhesus monkeys (Morrill and Peters, 2003). It does not revert in serial passage in mice and is non-pathogenic in hamsters (Rossi and Turrell, 1988). The virulence of the RVF vaccine strain was shown to be attenuated for cattle, including pregnant and lactating cows; sheep, including pregnant animals; and young lambs of seven days of age (Morrill, et al., 1991; 1997a).

Experimentally, vaccine strain can be transmitted by mosquitoes after oral pledget feeding or inoculation (Turrell and Rossi, 1991). However, because of the very low viremia following vaccination (Peters CJ, unpublished), it is unlikely that mosquitoes would become infected upon feeding on a vaccinated animal.

6.2 Fate of the Vaccine in Target and Non-Target Species

The RVF Modified Live Virus vaccine has been found to be safe in humans and animals. Safety of the vaccine strain has also been established by inoculation in pregnant cattle, and sheep and young lambs (Morrill, et al., 1991; 1997a). In another study, no signs of clinical disease were observed in any of the monkeys, following inoculation of RVF vaccine (Morrill and Peters, 2011). Safety of the vaccine strain has not been tested in immunocompromised humans, pregnant women, and children. Natural transmission of the vaccine strain could not be accomplished in research studies, using vaccinated sheep that were exposed to mosquitoes by USDA researchers (Dr. William Wilson, Pers. Comm.).

Reversion to Virulence studies have demonstrated that the recovery of live vaccine virus after vaccination is difficult, even in young animals inoculated with doses 1000 to 100,000 times the MID. Data have shown that recovery of virus declines rapidly and in parallel with the development of antibodies to the vaccine.

The vaccine virus is rapidly recognized by a vaccinated host, and protective antibodies are detectable within four days. Loss of detectable virus levels corresponds with developing levels of antibody against RVF. Virus could not be recovered from blood after 7 days. Thus, at 21 days post-vaccination (withdrawal period proposed for the vaccine), cattle cannot transmit virus.

The Summary Report of Data from a Pfizer's pilot study demonstrated that the recovery of the vaccine virus from blood was variable, even in very young animals (7 positives out of 60 samples), but recovery from liver homogenates was more reliable (8 positive out of 8 samples) during the first few days post-vaccination, leading to the selection of liver as the target tissue and Day 4 for the collection of samples in the pivotal reversion to virulence cattle study. These observations were consistent with results from previous studies that were conducted on this virus.

6.3 Potential for Shed and/or Spread from Vaccinate to Contact Target and Non-Target Animals

Shed and spread capabilities of the RVF vaccine strain are indicated in section IV.F.2. The virus was not isolated from serum, nasal, or fecal samples (Pfizer Study Report). In the same study, calves vaccinated with various doses of the RVF vaccine strain virus were commingled with sentinel animals. While all vaccinated animals seroconverted to the vaccine strain, none of the sentinel animals seroconverted, indicating no spread of the vaccine strain from vaccinated to susceptible animals.

6.4 Reversion to Virulence Resulting from Back Passage in Animals

The vaccine strain was shown to be attenuated for sheep, cattle, lambs, pregnant sheep, and cattle, and fetal calves (Morrill, et al., 1991; 1997a; 1997b).

Pfizer Study Reports on reversion to virulence of RVF vaccine strain in calves and lambs, along with four University of Texas Medical Branch (UTMB) supporting reports, were reviewed by CCVB in support of lack of reversion to virulence. These studies were previously submitted to the USDA-CVB on January 26, 2012. Additional information was supplied on April 11, 2012 in a study report on optimization of recovery of the vaccine strain virus. Together, the submissions were filed as acceptable in fulfillment of CVB requirements for demonstration of a lack of reversion to virulence and lack of shed and spread, and the Master Seed Virus was approved for use in manufacturing of this vaccine, which is destined for use in non-pregnant cattle and sheep. The study outcome of no clinical signs in the cattle and sheep experiments, the lack of seroconversion in contact animals, the performance history of the Pfizer RVF vaccine strain, and its well documented non-virulence in the scientific literature support inability of the RVF vaccine strain to revert to virulence.

6.5 Effect of Overdose in Target and Potential Non-Target Species

The MID of the vaccine virus was established in a study (Pfizer Study Report). The study also included a group of cattle inoculated with 1000-fold higher dose of the vaccine virus than the minimum protective dose. At 1000 fold above MID, no significant adverse events were observed in cattle. Another small study was conducted to permit the generation of antisera to RVF for use at the Pfizer laboratories. Cattle in this study were administered with doses 100,000 times greater than the MID. No significant adverse events were observed in these cattle, indicating that use of this strain in cattle is safe.

6.6 The Extent of the Host Range and the Degree of Mobility of the Vector

Host range and specificity is indicated in section IV.F. The vaccine is not biotechnology-derived, and no vector was involved in the construction.

RVF is naturally carried by mosquitoes in endemic areas, acting as vectors to transmit the virus to livestock. Infected livestock can in turn infect other mosquitoes. Laboratory tests have shown that a few of the mosquito species that can transmit the virus are found in specific regions in Canada. Thus, potential vectors for RVF exist in Canada, but the risk of these mosquitoes naturally transmitting the virus is low. The presence of an epidemic among animals can lead to illness among humans who are exposed to the diseased animals and infected mosquitoes.

Pfizer's studies have suggested that the RVF vaccine strain virus does not transmit from vaccinated to susceptible animals; only some of the vaccinated animals show transient viremia, and it is unlikely that mosquitoes feeding on vaccinated animals would become infected and have the ability to transmit the disease to susceptible animals or humans.

6.7 Relative Safety When Compared with Conventional Vaccines

The RVF vaccine is a Modified Live Virus conventional vaccine and is not biotechnology-derived. It has been found to be safe in all studies to date, except for studies in mice that remain slightly susceptible to high doses of the vaccine strain. Studies in all other species, including humans, have shown the vaccine to be safe.

The virulence of the RVF vaccine strain was shown to be attenuated for pregnant sheep and cattle, and fetal calves (Morrill, et al., 1991; 1997a; 1997b). Nevertheless, the vaccine will be used for vaccinating healthy cattle aged three months or over and is not intended to be used in pregnant animals.

7. Affected Environment

7.1 Extent of Release into the Environment – Identify Site

The study will be conducted at a commercial feedlot in Canada.

7.2 Persistence of the Vector in the Environment/Cumulative Impacts

No vector was used for the construct of the vaccine virus strain.

7.3 Extent of Exposure to Non-Target Species

Refer to section IV.F.

7.4 Behaviour of Parent Micro-Organisms and Vector in Non-Target Species

The wild-type RVF virus is transmitted by mosquitoes. Outbreaks in livestock are associated with rain and flood seasons in Africa and correlate to transient increases in mosquito-breeding environments. The wild-type virus is very stable in serum and can be recovered after 3 hours of exposure to 56°C. It may persist in infected livestock carcasses. No rodent reservoirs of the virus have been identified. The RVF vaccine strain was demonstrated to be stable at 4°C for several days. No long-term room temperature stability of the virus has been examined.

No vector was used for the construct of the vaccine virus strain.

8. Environmental Consequences

8.1 Risks and Benefits – Analysis of Potential Risks Compared with Benefits of Proposed Action/Vaccine

The RVF vaccine is a Modified Live conventional vaccine that was originally developed for use in humans. No risk has been identified with using the vaccine. The field safety study will allow for an evaluation of vaccine safety in the field as a final step before conditional licensing.

Wild-type RVF virus is a known zoonotic pathogen, listed on the U.S. Select List of Pathogens, and is the cause of an acute disease of domestic livestock in Africa and Madagascar. It is expected that, after licensure, a vaccine supply will be maintained as part of a DHS/USDA stockpile to use if a RVF outbreak were to occur in the U.S. Conditional licensure of this vaccine is being considered to provide the CFIA with an additional tool to control this disease, should an outbreak occur in Canada.

8.2 Relative Safety Compared with Other Vaccines

There are no other RVF vaccines on the market in the U.S. or in Canada. Based on available data, this vaccine is expected to be both safer and more effective than the commercial vaccines that are currently available in Africa.

9. Mitigative Measures

9.1 Worker and Non-Worker Human Safety

RVF is a known zoonotic pathogen, with the wild-type virus included in the U.S. Select List of Pathogens. The vaccine strain was developed initially by the U.S. Army as a potential human vaccine and has been tested in humans with no known adverse events. The vaccine virus is considered a BSL-2 risk. Safety of the vaccine strain has not been tested in immunocompromised humans, pregnant women, and children. Efforts should be made to avoid accidental exposure to the vaccine strain.

9.2 Handling of the Vaccine

Required Precautions and Personal Protective Equipment:

  • lab coat: yes
  • mask: not required
  • gloves: yes, impervious to aqueous
  • safety glasses: yes
  • goggles: not required
  • laboratory work: in Biosafety cabinet BSL-2
  • full face shield: not required
  • double gloves: not required

Other:

  • Handle as BSL-2 infectious agent.
  • Be aware that its safety in pregnant immunocompromised humans is unknown.
  • Prevent exposing pregnant or immunocompromised humans to reconstituted vaccine.

9.3 Handling Vaccinated or Exposed Animals

No extraordinary precaution is needed to manipulate the animals. Test animals will be sold for slaughter at the conclusion of the study, provided that the 21-day vaccine withdrawal period, as well as any additional withdrawal time required in the case of an animal having veterinary treatment during the in-life phase of the study, has been completed.

10. Monitoring

10.1 General

The vaccine licensing regulations in Canada require manufacturers to report all significant suspected adverse reactions to the CFIA within 15 days of receiving notice from an owner or a veterinarian. Veterinarians may also report suspected adverse reactions directly to the CFIA. If an adverse reaction complaint is received by the CCVB, the manufacturer is asked to investigate and prepare a report for the owner's veterinarian and the CFIA. If the problem is resolved to the satisfaction of the veterinarian or client, usually, no further action is requested by the CCVB. However, if the outcome of the investigation is unsatisfactory, the CCVB may initiate regulatory action, depending on the case, which may include further safety testing, temporary stoppage of product sales, or product withdrawal from the market.

10.2 Human

For the conduct of the field safety study: A draft Material Safety Data Sheet was provided to the study site investigator. Vaccine-handling instructions were provided to those who were involved in the study. The study protocol calls for the standard BSL-2 level precautions and the additional caution of exclusion of pregnant or immunocompromised individuals from exposure to the vaccine, as risks in individuals in those categories have not been studied.

For the use of the licensed vaccine: No special monitoring of the human safety of the product will be carried out.

10.3 Animal

For the conduct of the proposed study: Monitoring of animals will be carried out, as explained in the study protocol submitted to the CCVB. On study days 0 through 21, all animals will be observed daily for general health. For any abnormal health observation, a treatment will be prescribed, if necessary. All observations of abnormal health will be recorded. If injection site reactions (ISRs) are clearly visible during the daily observation period, the size will be visually estimated and recorded. If more than 10% of the study animals are observed to have ISRs during the 21-day observation period, all study cattle will be moved through an animal-handling facility to evaluate the injection site area in all enrolled animals. If ISRs are observed to persist past day 21 and do not appear to be resolving, extension of the study observation period could be warranted.

Any adverse reactions, not otherwise captured as part of the procedural data collection, will be documented and reported promptly. Adverse reactions will be observed and monitored through resolution. If an animal dies while on study, a necropsy will be conducted to determine the probable cause of death. The investigation into the death will include serological testing and other diagnostic activities, as appropriate, including an attempt to isolate vaccine virus. Any animal removed from the study will be documented and euthanized, with the carcass disposed of following standard procedures for the investigator and the feedlot.

At the end of the study, animals will be sold for slaughter, provided that the 21-day vaccine withdrawal period, as well as any additional withdrawal time required in the case of an animal undergoing veterinary treatment during the in-life phase of the study, has been completed.

Pfizer will work with the CCVB and the CFIA to obtain an experimental slaughter clearance prior to animal slaughter. To facilitate observations during the slaughter process, slaughter will be arranged at one slaughterhouse for all minimum age animals and a separate slaughterhouse for all market weight study animals. The details of location and time of slaughter will be provided to the CCVB and the CFIA in advance to allow for arrangements to have observers present. If the inspectors observe any sign of pathology at the time of slaughter, samples of the tissues will be collected and sent to an appropriate laboratory for evaluation.

Using the experimental vaccine: Veterinarians, vaccinators, and producers should report any suspected adverse reactions to the CCVB as indicated above. Suspected adverse reactions should be reported, using Form CFIA/ACIA 2205 – Notification of Suspected Adverse Events to Veterinary Biologics.

11. Consultants and Contacts

Pfizer Animal Health Canada Inc.
17,300 Trans-Canada Hwy
Kirkland, QC H9J 2M5
Telephone: 1-800-461-0917
Email: order_desk@zoetis.com

12. Conclusions and Actions

RVF is an arthropod-borne viral disease that is native to Africa. Researchers have demonstrated that most of the native North American mosquito species are capable of transmitting RVF. With the recent example of the spread of West Nile Virus across the North American continent after an accidental transmission, it appears likely that a similar event could occur with RVF. Outbreaks of RVF in countries in the Middle East (e.g. Israel), where RVF is not endemic, have been successfully controlled through an aggressive vaccination program. 

The vaccine strain is the only strain of RVF that is excluded from the U.S. Select Agent list, when used for the purpose of developing a licensed vaccine. The vaccine strain was attenuated and was not subjected to any molecular biological procedures. Hence, this vaccine is not biotechnology-derived and is considered as a modified live virus conventional vaccine. Literature and various studies on the RVF Modified Live Virus vaccine have shown the vaccine strain to be safe and protective in humans and animals. No reversion to virulence or shed and spread has been observed.

Natural transmission of the vaccine strain could not be successfully accomplished in research studies. The vaccine is proposed to be used only in healthy, non-pregnant cattle three months of age or older, for which safety of the vaccine strain has been established in several published reports and studies conducted by Pfizer. A 21-day withdrawal time is proposed for the vaccine, because the virus could not be recovered from blood after 7 days, and 21 days is the standard withdrawal time for a live vaccine.

Studies so far have indicated that RVF vaccine strain produces very mild transient viremia in vaccinated animals. It is, therefore, unlikely that mosquitoes would become infected by feeding on the vaccinated animals and transmit the infection to a susceptible population. There is no evidence of reversion to virulence of the RVF vaccine strain following inoculation in calves and lambs. To further eliminate the chances of spread of the vaccine virus, the proposed field safety study will be conducted in the non-vector season, with disposal of the animals that are used soon after completing the study.

With the demonstrated possibility of an outbreak of RVF somewhere in North America, the proactive licensing of a vaccine and the maintenance of a vaccine stockpile are reasonable actions that are necessary to protect the North American food supply from this risk. This work was initiated at the request of the U.S. government and is of equal interest to Canada.

Keeping in mind all factors mentioned in this environmental assessment, Pfizer Animal Health Canada Inc. may be allowed to conduct the proposed field safety study in Canada. The conditions of use of the vaccine will be documented in a Permit to Release Veterinary Biologics (PRVB)prior to the start of the field safety study and will specify the conditions for release of this experimental vaccine in the environment. The PRVB will also stipulate requirements for immediately stopping the study and informing the CCVB of any significant adverse events, attributable to the vaccine, that are observed.

13. Bibliography

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Giorgi C, Accardi L, Nicoletti L, et al. Sequences and coding strategies of the S-RNAs of Toscana and Rift Valley fever viruses compared to those of Punta Toro, Sicilian sandfly fever, Uukuniemi viruses. Virology 1991;180:738-53.

Kortekaas J, Zingeser J, de Leeuw P, et al. Rift Valley fever vaccine development, progress and constraints (Conference summary). Emerg Infect Dis 2011;17:9.

Morrill JC, Carpenter D, Taylor HH, et al. Further evaluation of a mutagen attenuated RVFV in sheep. Vaccine 1991;9:35.

Morrill JC, Mebus CA, Peters CJ. Safety and efficacy of a mutagen attenuated RVFV in cattle. Am J Vet Res 1997a;58(10):1104-9.

Morrill JC, Mebus CA, Peters CJ. Safety of a mutagen-attenuated Rift Valley fever virus vaccine in fetal and neonatal bovids. Am J Vet Res 1997b;58(10):1110-14.

Morrill JC, Peters CJ. Protection of MP-12 – vaccinated rhesus macaques against parentral and aerosol challenge with virulent Rift Valley fever virus. J Inf Dis 2011;204:229-36.

Morrill JC, Peters CJ. Pathogenicity and neurovirulence of a mutagen-attenuated Rift Valley fever vaccine in rhesus monkeys. Vaccine 2003;21:2994-3002.

Rossi CA, Turrell MJ. Characterization of attenuated strains of Rift Valley fever virus. J Gen Virol 1988;69:817-23.

Swanepoel R, Coetzer JAW. Rift Valley fever. In a chapter from infectious diseases of livestock with special reference to Southern Africa vol. 1.

Turrell MJ, Rossi CA. Potential for mosquito transmission of attenuated strains of Rift Valley fever virus. Am J Trop Med Hyg 1991;44(3):278-82.

Von Teichman B, Engelbrecht A, Zulu G, et al. Safety and efficacy of Rift Valley fever Smithburn and Clone 13 vaccines in calves. Vaccine 2011;29:5771-7.

Pfizer Study Reports – In addition to the above-mentioned research articles, several study reports submitted by Pfizer Animal Health Canada Inc. were consulted, or reviewed, for preparation of this document.

Following preparation of this environmental assessment, the name of Pfizer Animal Health Canada Inc. has changed to Zoetis Canada Inc.

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