Safety and efficacy profile of commercial veterinary vaccines against Rift Valley Fever disease
Rift valley fever (RVF) is an infectious illness with serious clinical manifestations and health consequences in humans and a wide
range of domestic ruminants. The virus transmitted either by mosquito bites or through exposure to blood, body fluids or infected
animal tissues. As with other viral diseases the prevention and control of RVF relies heavily on immunization of susceptible herds
with safe and cost-effective vaccine, that able to confer long-term protective immunity. Interestingly, several strains of RVF vaccines
have been developed and available in commercial production. The two most prominent among these vaccines are Formalin-Inactivated
vaccine, and live attenuated Smithburn vaccine. Although, both are immunogenic and widely used in control programs, they proved to
be accompanied by significant concerns. The first one requires multiple doses for protection, and the other has been reported to cause
abortion and fetal malformation in pregnant ewes, as well as a possible reversion to virulence. Recently, a newly described RVF vaccine
registered and extensively used in South Africa and Namibia named Clone13. Safety and efficacy trials proved the vaccine as safe
in pregnant ewes as highly immunogenic, along with its potential for differentiating infected from vaccinated animals(DIVA).
In conclusion, with the exception of Clone13 vaccine, RVF vaccines presently available in markets are not fulfill the requirements of
safety and potency. Various novel candidate vaccines against RVF are under development, presumably safer and more immunogenic
than currently available in markets, have not seen the light yet. Consequently, incentive plans should be introduced to companies to bring
those promising candidates to markets.
RVF, Live Vaccine, Clone 13
Rift valley fever (RVF) is a life-threatening disease of domestic
ruminants and humans, included in OIE list as a notifiable and
transmissible disease of serious socio-economic impacts and public
health concerns. The causative agent is mosquito-borne virus
belongs to the family Bunyavirridae, genus phlebovirus . It was
first reported among livestock in Kenya in 1931, since then it has
been reported as occurring in most African countries . The first
appearance of RVF virus in new geographical areas outside Africa
was reported in Jazan region, south-west Saudi Arabia in 2000,
with 886 confirmed cases involving 124 deaths . The socioeconomic
impact of the RVF epidemics has been higher specially
to populations who were totally dependent on livestock income.
The negative impacts not only affecting livestock producers, but
also extended to various stakeholders in the marketing chain
including, livestock traders, slaughterhouses, casual laborers,
butchers and non-agricultural sectors ,.
As there is no specific treatment for RVF, vaccination of
susceptible animals with safe and cost-effective vaccine during
non-epidemic periods, remains the only effective method to build
sufficient immunity able to limit the overall scope of epidemics
and preventing viral human infections. Although, several
adverse effects had been associated with vaccination , the numerous advantages and the benefits derived have promoted
the use of vaccines rather than chemotherapy. Apart from the fact
that vaccination is the only available method to prevent viral
infections in the absence of broad spectrum antiviral, they
are mostly environmentally friendly and contribute indirectly
to preventing drug resistance and pharmaceutical residues in
food . Furthermore, they have a significant impacts not only
on reducing losses or improving health and production, but
also on human health through increasing safe food supplies and
preventing zoonotic diseases .
A successful vaccination program depends on a proper selection
for the vaccine, as well as, good handling practices (in accordance
with manufacturer’s instruction). Vaccine type and timing should
be done according to the epidemiological aspect of targeted
area. Generally, live attenuated vaccines are more preferable to
inactivated ones in endemic zones and considered the primary
available option for controlling the disease in high risk areas
during inter-epizootic period or at an outbreak warning. While,
inactivated vaccines are recommended specifically in free areas.
However, during an outbreak time of RVF disease, vector control,
public education, quarantine , slaughter pan , probably are the
most effective measures against the disease.
Obviously, commercial production of good quality vaccines
tend to be a biggest challenge, as the cost of sustained
vaccination campaigns against RVF, is beyond the capacity
of most countries suffering regular outbreaks. Additionally,
outbreaks of RVF usually occurred at irregular intervals and
most commonly following exceptionally heavy rains, these events
have led to refuse annual vaccination during long inter-epizootic
periods which in turn both decreases the demand for vaccines and
preventing the manufacturers from maintaining strategic stocks
due to limited shelf-life.
Reliable information about vaccination in endemic zones are
scarce. With the exception of Saudi Arabia, South Africa and
Egypt, all affected countries have not practiced routine vaccination.
In Egypt control of RVF, based on alternation between live
and inactivated vaccines concurrent with periodical vector control.
Live vaccine had been used at intermittent periods before, during
or after outbreaks in unidentified manner might be a significant
factor in disease persistence and maintaining endemicity of RVF
In Saudi Arabia, a control program based on sustain vaccination
campaigns, along with vector control has been implemented,
since the disease was first recognized. Despite, some
serological evidences of RVF occurrence, vaccination seems to
play a significant role in control, as long as, no clinical disease in
humans and animals has been reported yet .
Presently, two main types of vaccines with different development
techniques are available for immunization against RVF, including,
live attenuated vaccines and in-activated vaccines. Attenuation
of live vaccines was accomplished by in-vitro passage through
a series of cell cultures so as to produce a version of a virus
attenuated to such a level unable to cause disease in animals,
together with inducing a rapid onset of long lasting immune
response similar to that of natural infection. While, inactivation
obtained by growing thevirus in culture media before treated with
heat or chemicals such as Formalin to destroy the ability of viruses
to replicate. Although, inactivated vaccines are biologically
safe, more stable and have no residual viruses or risk of reversion
as attenuated vaccines, they are known to be less protective,
needed high antigenic mass and strong adjuvant to stimulate the
immune system. Moreover, they continued to be associated
with slow onset of immunity, local reactogenicity and residue,
risk of incomplete inactivation, hazards to personnel , as well as,
not very efficient without multiple injections.
To date, there is no licensed vaccines against RVF available to
immunize humans, while various strains for livestock now
licensed and commercially produced including Smithburn vaccine,
Formaline-inactivated vaccine and Clone13. These vaccines
produced by three different laboratories: Onderestepoort
biological products limited(OBP) in South Africa, Kenya
veterinary vaccine producing institute (KEVEVAPI), and Egypt’s
Veterinary Serum and Vaccine Research Institute(EVSVRI).
The objectives of this review is to: (1) summarize commercially
available RVF vaccines for veterinary use in Africa and Arabian
peninsula,(2) highlight the safety-efficacy profile and drawbacks
of these vaccines according to previous safety-efficacy trails,(3)
review different vaccination strategies adopted in countries
experiencing RVF outbreaks. Table (2)
Smithburn vaccine strain is derived from the virulent Entebbe
strain, isolated from mosquitoes in Uganda and developed by serial
passages in mouse brains to be able to induce immunity in ewes
and their offspring after subcutaneous inoculation. Currently,
produced in OBP and KEVEVAPI in freeze-dried form.
The recommended dose is 1ml of the reconstituted vaccine
administered via subcutaneous route for the immunization of
sheep, goats and cattle. According to manufacturer’s instructions,
the vaccine can cause abortion or fetal malformation in a small
percentage of animals, particularly sheep, as well as, a slight
febrile reaction may occur on the second to fourth day following
inoculation. Accordingly, the use should be restricted to nonpregnant
animals above six months age before or at the mating
season so as to ensure maternal antibodies and to avoid
abortion as well .
Despite, these adverse outcomes, it has been widely used for many
years as the major control measure as a cost-effective vaccine in
most endemic zones, since the first introduction of the virus.
likewise, in Jazan region, Saudi Arabia it has been used as the
gold standard vaccine for several years as a prevention and control
measure, since 2000 outbreak. It has also been proved through
serological surveys to be effective and highly beneficial in
controlling infections, as no notable clinical signs in animals nor
humans have been reported yet. Published efficacy studies conducted in the same region in sheep and goats reported that,
the vaccine was highly immunogenic and able to induce
long lasting antibodies, irrespective to variations among vaccine
batches. The level of herd immunity induced by smithburn strain
vaccine significantly declined with elapse of years. The percentage
of IgG positive animals declined from 95% to 66.7% after one year,
and it would declined to zero after six years and eleven months
. On the contrary, some safety and potency concerns associated
with smithburn vaccine.
The vaccine was neither able to produce
proper protective antibodies in all animal species particularly
cows, nor safe in immuno-compromised animals and pregnant
during gestation period leading to high abortion. Larger efficacy
and safety study conducted to investigate antibody response to
Smithburn vaccine in cattle reported that, twenty-eight cows out
of 120 pregnant cows and buffalos were aborted within three days
after vaccination. Moreover, the isolation of the virus from aborted
fetus has proved in utero transmission of the vaccine virus .
Furthermore, the vaccine virus not only causes abortion and
death of fetus at parturition, but also caused harmful changes in
internal organs and propagated inside hepatic cells in a manner
similar to natural infection.
The lyophilized vaccine containing 2%(HAS) was first
prepared in African green Monkeys Kidney cell and proved to
be immunogenic, highly resistant to thermal deterioration, and
could be used as reference vaccine. Commercially produced
from OBP and EVSVRI, the virus strain adapted for growth in
baby hamster Kidney(BHK-21)cell, with aluminium hydroxide gel
adjuvant for immunization of cattle , sheep, and goats, irrespective
to the age and stage of pregnancy. A safe version of inactivated
vaccines with minor side effects named TSI-GSD 200, was
developed in USA by using an new master seed of the Entebbe
strain to protect personnel who either work in laboratories or
would be exposed to RVF infection, after receiving three doses on
days 0,7 and 28, to provide good long immunity with neutralizing
antibody titers (1:140).
The safety and efficacy profile of
inactivated vaccines have been further investigated in several
trials. The immunization of susceptible cattle, sheep and goats with
inactivated vaccine would induce higher neutralizing antibodies
persisted for 9 month in cattle with evidence of protections against
virulent RVF virus in pregnant ewes. A comparative study
conducted to assess the response in cattle to live and inactivated
RVF vaccines revealed that, a booster dose of inactivated vaccines
after 5 months of the first vaccination was safe and able to
evoke a good response . Further studies conducted to evaluate
inactivated OBP vaccine as it is extremely difficult to maintain
low temperatures during vaccine transportation. The vaccine
was stored in different temperature(4C,25C, and alternation
between (4C AND 25C) for a week. It was found that the vaccine
was stable, well tolerated with mild or limited adverse reactions,
and induced long-lasting neutralizing antibodies may persist for 21
months post booster dose. at any age and any stage of pregnancy.
These neutralizing antibodies, Its efficacy not adversely affected
by variation in temperature during transportation,.
Although, Formalin-Inactivated vaccine and live-attenuated
Smithburn vaccine are widely used in control, both of them may
accompanied by safety problems. The first one requires three
doses for protection, and the second has a risk to cause abortion
and fetal malformation in pregnant animals . Drawbacks of
these vaccines stressed the need for alternative vaccines in terms
of safety and efficiency. Consequently, a massive progress and
several initiatives have been done for the evolution of modern
vaccines. Recent studies have shown that, RVF virus vaccines
containing deletions of the NSs and NSm genes are highly
attenuated, confer protective immunity with no detectable viremia
and could be useful in control of RVF virus in endemic regions,
as well as, allow for DIVA. The commercial OBP vaccine
named (RVF Clone13) was recently registered, marketed in a
form of Freeze-dried live attenuated virus (clone13 strain) and
extensively used in South Africa .
Clone13 is a naturally attenuated isolate of RVF virus with a large
deletion in the S segment. It was cloned by plaque purification of
non-fatal human case isolate (74HB59 strain), obtained during
1974 RVF outbreak in Central African Republic and proved to
be highly Immunogenic leading to long-lasting immunity as well
. Published efficacy and safety studies of clone13 vaccine have
shown that the vaccine protects animals properly without inducing
undesirable clinical signs, such as abortion in pregnant ewes,
pyrexia or fetal Malformation in their offspring . Recent
efficacy and safety studies conducted on sheep and goats in
Senegal stipulated that the vaccine was safe at stages of pregnancy
and didn’t induce adverse effects. Additionally, antibodies level
persisted up to 1year after vaccination . However, some
safety studies raised concerns about the possibility of Genetic
reassortant between S segment in Clone13 vaccine and virulent
strains in field .
Furthermore, little is known about the persistence duration of
antibodies to clone13 vaccine in sera. Although, the currently
available commercial vaccines have made a great contributions
to RVF control over the past 80years, they are associated with
safety and efficacy concerns, including, but not limited to : risk
of abortion- pyrexia- fetal malformation-teratogenic effects–
viraemia-risk of reassortment-short shelf life- revaccination
and risk of incomplete inactivation in killed vaccines. The gab
in the safety and immunity explains the need for new promising
candidates currently under development, such as subunit vaccines,
virus vector and replicons.
RVF vaccine quality control
Pan African Veterinary Vaccine Centre(AU-PANVAC) is a
recognized reference centre for vaccine quality control, involved
in certifying veterinary vaccines either produced or imported to
the continent in particular all batches of RVF vaccines, to being
in compliance with standards of potency and requirements of
quality assurance to ensure its purity, safety, efficacy and stability.
The production of good quality vaccine is critical for vaccination
strategies particularly in endemic zones. Interestingly, the quality control of RVF vaccines is assessed under Bio-safety level 3(BSL
3) laboratory due to potential for occupational infections.
Currently, two types of RVF vaccines were submitted to the centre
including, live-attenuated Smithburn vaccine and inactivated
vaccines prepared from virulent field strain. Tests performed to
certify the quality control of live RVF vaccine batches involving:
Freedom from bacterial, fungal and viral contamination.
Safety on susceptible animals and laboratory animals.
Identity test using Reverse Transcriptase-Polymerase Chain
Reaction. Potency using intra-cerebrally inoculation of
vaccine in infant mice or Vero Cells and assessment of immune
response on vaccinated sheep.
Stability test using assessment of potency after incubation of the
RVF vaccine at 37°C for one week. Residual Moisture content
using the gravimetric method. While tests for quality control of
inactivated RVF vaccines including:
Freedom from bacterial, fungal and viral contamination. Safety on
susceptible animals and laboratory animals.
Identity test using Reverse Transcriptase-Polymerase Chain
Reaction. Potency using assessment of immune response on
Completion of inactivation using inoculation of vaccine into
susceptible cell culture. Residual Inactivant content using
Table (2) Commercially available vaccines against RVF .
With the exception of Clone13, commercial vaccines that currently
available in markets are lacking safety, potency and potential for
DIVA . Live attenuated Smithburn reported to cause abortion
and fetal malformation in pregnant ewes. Formalin- inactivated
vaccine requires multiple doses for production. Even Clone13 has
a risk of potential reversion to virulence, and more studies from
different areas should be done to determine the duration persistence
of IgG antibody in sera of vaccinated animals There are ongoing
efforts to develop several novel RVF candidate vaccines involving
subunits vaccines, virus vector and replicons Incentives for
commercial companies to invest in vaccine development should
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