Research roadmap for coronavirus vaccine development

Download 202402 Draft Coronavirus Vaccine research roadmap Final

Naturally attenuated candidates

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1 Vaccine

Naturally attenuated candidates

Research Question

What are we trying to achieve and why? To develop safe and effective live attenuated vaccines (LAVs) for animal coronaviruses, e.g. those that infect pets, livestock, and wildlife. Addressing coronavirus infections in animals is vital to safeguarding food security, biodiversity, and public health
Problem: Current vaccine strategies often lack broad protection across viral strains or genera, limiting effectiveness. Live attenuated vaccines offer a promising solution by providing durable immune responses but need to be developed and optimized for safe, cross-species use whilst avoiding reversion and other associated issues.

Research Gaps and Challenges

Genetic stability: Ensuring that the virus remains stable and does not
revert to a virulent form
Understanding host-specific immunity: Different animal species, such
as livestock (e.g., pigs, cattle), pets (e.g., cats, dogs), and wildlife (e.g.,
bats, ferrets), have varying immune responses to coronaviruses and it
is not clear how much we need to understand these to design LAVs
across species
Strain diversity: Animal coronaviruses exhibit significant genetic
diversity, so it is difficult to design a universal LAV. Indeed, vaccine
candidates may need to be strain- or species-specific, limiting their
generalizability
Safety concerns: While LAVs can often provide strong immunity, they
may pose safety risks, particularly in immunocompromised animals.
Since they are LAVs, there is also the need to address if there is
potential for unintended transmission to non-target species (including
humans)
Mucosal immunity: For almost all vaccines, inducing strong mucosal
immunity (e.g., in the nasal or gastrointestinal tracts) is crucial. It is
unclear where LAVs stand within the spectrum of responses (are they
the best?)

Solution Routes

Rational attenuation through genetic engineering: Using reverse
genetics to target specific viral genes or cis/trans-acting sequences
involved in pathogenicity (e.g., non-structural proteins or accessory
proteins)
Cold-adaptation or temperature-sensitive mutants: LAVs that only
replicate at lower temperatures (such as those found in the upper
respiratory tract) may reduce the risk of systemic infection and
virulence, particularly for animals like pigs and cattle
Targeting mucosal immunity: Targeting LAVs to induce both systemic
and mucosal immunity by focusing on routes of administration (e.g.,
intranasal or oral vaccines) might improve the situation
Using corona LAVs as multivalent vaccine candidates: Could a single
vaccine targeting multiple viral strains or species-specific coronaviruses be developed, either by combining multiple attenuated strains into a single formulation or engineering multi-valency?

Dependencies

Enhanced surveillance and sequencing: Continuous surveillance of
circulating coronaviruses in animal populations (including genetic
sequencing) is essential to monitor emerging strains and assess the
potential for cross-species transmission. This is critical for updating and refining live attenuated vaccine strains
Animal models: Establishing reliable animal models for studying
coronavirus infections in pets, livestock, and wildlife is necessary for
preclinical vaccine testing. These models need to reflect the
physiological responses of different species to coronavirus infection
and vaccine response
Safety testing protocols: Development of standardized protocols for
evaluating the safety and genetic stability of live attenuated vaccines,
particularly in terms of reversion risk and potential transmission to
non-target species
Cross-species immune response studies: Detailed research into how
different species’ immune systems respond to coronavirus infection
and vaccination is required. This includes understanding differences in
innate, mucosal, and adaptive immune responses
Regulatory frameworks: Clear regulatory pathways for the approval and deployment of live attenuated vaccines in animals, particularly for wildlife species, need to be established
Rational attenuation through genetic engineering: Using reverse genetics to target specific viral genes or cis/trans-acting sequences involved in pathogenicity, such as for non-structural proteins or accessory proteins, requires knowledge of what these are

State Of the Art

LAVs have been successfully developed for porcine epidemic diarrhoea
virus (PEDV) in pigs, and BCoV for cattle, leading to widespread use.
However, issues with incomplete protection and viral shedding remain
concerns. Failures in cross-protection between strains highlight the
need for updated and multivalent approaches. LAVs for cats have
shown some promise, but issues with strain-specific immunity and
adverse reactions persist. People are exploring LAV candidates for
controlling SARS-CoV-2 in animals, e.g. cats/mink that are known
reservoirs or spillover risks. Bivalent CoV and rotavirus vaccine (CalfGuard) has been shown to be effective for use in cattle against
betacoronavirus
A multivalent (IBV, NDV, egg drop syndome virus) inactivated vaccine
has been produced against gammacoronavirus in poultry (Nobilis IB +
ND + EDS)
A bivalent (TGE virus and rotavirus) vaccine has been shown to be
effective against alphacoronavirus in pigs (ProSystem TGE/Rota).
A multivalent (CoV, adenovirus, parainfluenza, parvovirus) vaccine has
been shown to be effective against alphacoronavirus in dogs (Solo-Jec
6)
A monovalent vaccine has been shown to be effective against
alphacoronavirus (FIP) in cats
What failures do we know about?
Attenuated virus would most likely only work in immune naive
individuals, so a non-replicating platform would be better and also
safer