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Risk Assessment
Record information and status
Record ID
113493
Status
Published
Date of creation
2016-06-24 14:28 UTC (gutemberg.sousa@mctic.gov.br)
Date of publication
2018-06-15 13:36 UTC (dema@itamaraty.gov.br)

General Information
Country
  • Brazil
Title of risk assessment
Risk Assessment Bovela® Modified Live Vaccine against Type 1 and Type 2 Bovine Diarrhea Virus
Date of the risk assessment
2015-06-10
Competent National Authority(ies) responsible for the risk assessment
National Technical Biosafety Commission
Setor Policial Sul -SPO Área 5 Quadra 3 Bloco B - Térreo Salas 10 à 14
Brasília, DF
Brazil, CEP - 70610-200
Phone:(5561) 3411-5516
Fax:(5561) 3317-7475
Email:ctnbio@mct.gov.br
Url:National Technical Biosafety Comission
Contact details of the main responsible risk assessor
Dra Maria Sueli Felipe Soares
President
National Technical Biosafety Comission (CTNBio)
Setor Policial Sul -SPO Área 5 Quadra 3 Bloco B - Térreo Salas 08 à 10
Brasília, DF
Brazil, CEP - 70610-200
Phone:(5561) 3411-5151
Fax:(5561) 3317-7475
Email:msueliunb@gmail.com
Url:National Technical Biosafety Comission
Risk assessment details
Living modified organism
Bovela® Vaccine
Dra Patrícia Schwarz Production of medical or pharmaceutical compounds (human or animal) - Vaccines
Scope of the risk assessment
  • vaccine
Risk assessment report / Summary
Methodology and points to consider
Potential adverse effects identified in the risk assessment
It is known that BVDV is not infectious to human beings, has no zoonosis potential and has no
influence in human health according to OIE - World Organization for Animal Health, 2008.
Toxic and allergic effects have not been reported in the literature. BVDV has no ability to infect
human cells even when such cells are induced to express receptors that are BVDV, such as
bovine CD406. This strengthens the firm barrier that prevents BVDV to infect human beings.
Vaccines strains are unable to infect the human being, and thus are not pathogenic to humans,
independently of age, health condition or immune status of the individual.
Excipients that are part of the vaccine composition are not pharmacologically active and fail to
have any toxic effect after human being exposure. All excipients are described in the
pharmacopeia (Farm Eur), and are commonly used in medications for human consumption.
Salts (WPBS and physiologic saline) and sugar (sucrose) have no biologic relevance and are
metabolized by the organism.
A vaccinated animal that has its general condition affected by immunosuppression or concomitance with other disease may not have a normal immune response to the vaccine. The
deletions within the genome did not increase susceptibility to immunosuppression.
The vaccine organism does not integrate its genome to the host genome DNA. Viruses BVDV-1
and BVDV-2 belong to the family Flaviviridae and are formed by one single-stranded positive
sense RNA. Replication of the viral genome occurs in the cytoplasm of the infected cells. The
life-cycle does not include DNA intermediation and the viruses do not express the reverse
transcription. Therefore, DNA recombination of the host cell is not expected.
The BVD type 1 master seed, P05022006 BVD, and BVDV type 2 master seed, ddBVD Tub
2 MSV, batch P14022806, 15/03/06 failed to revert to virulence and are safe to be used in the
production of modified live vaccines according to the results observed in studies "nº 6131-
0955-06B-90 - Virulence reversion safety study for bovine viral diarrhea type 1 virus double
deletion master seed" and "nº 6131-0955-06B-034 - Virulence reversion safety study for
bovine viral diarrhea type 1 virus double deletion master seed". Briefly, both studies pursued
to show that there was no reversion to virulence of the BVD type 1 of type 2 master seed with
double deletion. A reverted passage model using newborn calves that have not received
colostrum and were free from viruses and maternal antibodies passed via the colostrum. The
study findings showed that there was not reversion to virulence after 2 and 3 reverted
passages for BVDV-2 and BVDV-1, respectively, with any indication of active infection by BVDV.
Studies conducted in pregnant animals showed that vaccination of milk cattle with a BVDV
vaccine made from one strain of BVDV-1 and another with a BVDV-2 strain is safe in pregnant and non-pregnant cows. The vaccination has no effect to conception rates. Regarding efficacy,
due to different findings, there is indication of protection in the group vaccinated against field
infection by BVDV.
As far as the persistent BVDV infection, it was not established in any of the fetuses and failed
to be recorded any influence on the normal development and/or newborns that could be
ascribed to this vaccination. There was no record of systemic reaction or grave site after
treatment with the vaccine. Based on the results of one of the studies, we can conclude that
administration of an overdose of ten times the vaccine with BVDV-1 and BVDV-2 in pregnant
female calves in the two semesters of pregnancy is safe.
The Bovela® vaccine is not expected to interfere in the efficacy of other vaccinations, though
the use of this product with other vaccines is not recommended.
Likelihood that the potential adverse effects will be realized
BVDV has low survival ability to survive outside of its host, since it requires a living cell to
replicate. BVDV was totally inactivated within a period of 3 weeks at 5oC, 3 days at 20oC and 5
minutes at 50oC in bovine manure and in a pH lower than 5.7 and higher than 9.3. Besides,
solar radiation can inactivate members of the Flavivirus family in a matter of days. The cycle of
this virus does not have a DNA phase (fails to possess reverse transcriptase coded in its
genome, since it is not a retrovirus) and the host cells also fail to produce RT. RNA is the only
genetic material, and this does not make recombination with the host DNA possible. Therefore,
the risk that the viral genome be genetically transferred to the genome of vaccinated animals or to any other animal or environmental or nosocomial bacteria is very low.
Possible consequences:
Clinical studies in bovines with each strain of the vaccine were conducted, showing that:
1) immunization started after 3 weeks with 104 TCID50 of the vaccine in 3 years old cattle;
2) immunity lasted for 12 months for both vaccines; 3) the time of OGMs detection in
vaccinated animals showed that the viruses were present in lymphoid organs up to the 13th day
after vaccination and in bovine respiratory and gastro-intestinal tissues up to the 6th to the 9th
day after vaccination; 4) viremia was recorded between days 6 to 20, and for no longer than
the 14th day after vaccination; 5) the modified virus was found in milk traces of vaccinated
cows (between days 6 to 23 DAV), though there is not transmission of the virus by milk, since
there was no positive serologic response in calves fed with the milk containing the vaccine
virus; 6) infections in human beings is not possible since human cells do not possess CD-46, the
viral bovine BVDV receptor; 7) there was no reversion to virulence in BVDV virus types I and II,
being therefore their use safe in the production of modified viral vaccines; 8) the vaccines are
safe to pregnant cows in all phases of the pregnancy and there was not recorded any impact in
conception rate, as well as any influence on fetal development (no teratogenic effects);
9) Although the report mentions in its reference list two studies (numbered 2209054 and
2009055) on assessment on duration of fetal protection, the report fails to clarify whether in
fact Bovela® provides transplacental protection to the fetus; this point could have been
explained in greater detail; 10) live vaccine type I and type II strains provide safety and efficacy
to milk cattle vaccination in all stages of pregnancy, in not pregnant cattle and also in programmed insemination animals; 11) there was no detection of virus in the nasal secretion
(which could result in horizontal transmission to the environment), blood, urine, feces in every
moment of the studies.
BVDV is an enveloped virus and fails to present resistant structures that may survive, having
low survival abilities outside its host. The virus integrity and stability is strongly affected by
sunlight (UV radiation), detergents, temperature and pH. Both Bovela® vaccine sylvan and
modified BVDV may be inactivated by bleach, alcohol and detergents.
Mutations and deletions that are present in attenuated strains of BVDV-1 and BVDV-2 vaccines
help the immune system by developing an adequate response to eliminate the virus. There are
no scientific evidences of increased ability of transmission of attenuated BVDV virus for nontarget
species.
Estimation of the overall risk
Data from scientific literature and results of experiments conducted and submitted by the
applying company show that the vaccine Bovela® fails to bring any significant risk to the
environment, that it is safe for human and animal health, talking in considerations:
1- Modified viruses BVDV-1 and BVDV-2 (master seed) fail to present reversion to
virulence and the attenuated phenotype is stable;
2- BVDV is no infectious to human beings, does not affect human health and has no
zoonosis potential;
3- Vaccine strains were generated by deletions in two genes of the viral genome, Npro
and Erns, with no additional external sequence, which means that the transfer of sequences
that do not belong to BVDV would be impossible to occur;
4 - Besides, once the BVDV genome is contains just RNA, and has no codification for
reverse transcriptase, the potential of genetic transfer to other species' genome is null;
5- Despite the necessary challenge to immunologic protection, due to the heterogeneity
existing between the strains of BVDV, both vaccines (live-modified or dead) has proven efficacy
in controlling the disease. The vaccination is not 100% effective in each animal, while being
effective at the herd level. Although dead vaccines are potentially safer than live vaccines, the
latter are less effective and require frequent boosters (at least twice each year).
6 - BVDV is an enveloped virus and fails to have resistant structures that may survive,
showing low ability of survival outside its host. Virus integrity and stability is strongly affected
by sunlight (UV radiation) detergents, temperature and pH. Both sylvan and modified viruses of
the Bovela® vaccine may be inactivated by bleach, alcohol and detergents,
minimizing/eliminating the likelihood of causing environmental harm
Recommendation(s)
Regarding the post-commercial releasing, CTNBio determines compliance with instructions
and conduction of technical monitoring actions mentioned by CTNBio Ruling Resolution no. 09,
of December 02, 2011.
Need(s) for further information on specific issues of concern
PCR data obtained for MVS and WVS (MVS + 5) of strains in vaccines of modified BVDV have
also confirmed the presence of the introduced Npro deletion. The in vitro data were also
supported by PCR data obtained in BVDV (virus isolation method) positive samples which
showed that the introduced Npro deletion remained stable for several in vitro passages. Jointly,
the data show that BVDV genomes containing the inserted deletions are genetically stable in
vitro and in vivo.
Receiving environment(s) considered
BVD is considered one of the most significant infectious diseases in the livestock industry worldwide due to its high prevalence
LMO detection and identification methods proposed
molecultar traditional methods

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