What
is biopharma doing to develop vaccines against Covid-19, and what are
the properties of each approach? Vantage takes a look.
While efforts to develop treatments for Covid-19 continue, it will
probably not be possible to declare the pandemic truly over until an
effective vaccine exists. Here numerous companies are also active, and a
Vantage analysis reveals nearly 25 projects that should be of special interest.
Among these an mRNA vaccine has seized the early lead, courtesy of Moderna, though Johnson & Johnson’s promise to develop an AAV vector-based approach on a non-profit basis might have the most promise. However, despite understandable enthusiasm, the road to having a vaccine approved is long and treacherous.
The need to build sufficient manufacturing infrastructure is just one aspect that will slow the process, and that is before a vaccine with a sufficient efficacy is developed. It could also take a while to find a product with the right mix of safety and ability to generate antibodies that offer sufficient protection.
A recent article by the Coalition for Epidemic Preparedness Innovation (CEPI) in the NEJM pointed to the industry’s ability to respond quickly to the need for pandemic flu vaccines, but said those against Sars had not followed a similar path. Additionally, Covid-19 is an RNA virus, and the industry’s vaccine efforts against this type of pathogen, notably RSV, have underwhelmed.
Early attention
It might surprise that in the coronavirus pandemic Moderna’s mRNA-1273, rather than more traditional vaccine approaches, has seized early attention. One key advantage of RNA (and DNA) vaccines is that they use synthetic processes and do not require culture or fermentation, offering much faster manufacturing.
Moderna itself claims that mRNA vaccines are better at mimicking natural infection, and highlights the “agility” of its manufacturing system. Production for a phase II trial could begin in a few months, and ultimately could allow millions of doses to be made.
Pfizer, which through a deal with Biontech hopes to enter the clinic with another mRNA vaccine this month, told Vantage: “We are working at record pace. While the development process can generally take years, we are working with partners and government agencies to find opportunities to save time wherever we can.”
Unique antigens
Mechanistically, a prophylactic vaccine works by exposing the immune system to antigens unique to the virus in question, seeking to prime the immune system for the quick generation of large amounts of antibodies in the event of an actual infection.
An mRNA vaccine, for instance, comprises mRNA that codes for expression of such a protein antigen. Different vaccines have different properties in terms of whether they generate humoral (B cell and antibody) versus cellular (effector T cell) immunity, and at which sites this is elicited.
Beyond the modality that each vaccine approach uses, and whether adjuvanting is needed to potentiate the immune response, a key consideration is clearly the choice of antigen.
By far the most popular approach has been to target epitopes on Covid-19’s spike protein, a structure found on the surface of the virus. Ideally, antibodies raised against this could bind the virus immediately and stop the infection of host cells. Some vaccines target other so far undisclosed epitopes or proteins.
The CEPI has outlined how carrying out multiple activities
simultaneously rather than linearly could curtail development times in a
pandemic, and J&J says an accelerated timeline could see its lead
vaccine being ready for emergency use in 2021.
That would represent an extraordinarily fast turnaround, but even so a vaccine of some sort might be needed even sooner. Thus even a suboptimal vaccine with moderate efficacy that could merely reduce the severity of Covid-19 infection might be a viable way of protecting people as next winter approaches, some think.
“It is hard to imagine fully returning to a pre-Covid-19 life until we have an effective vaccine, most of the population has been infected, or we have therapies that can turn nearly 100% of severe cases into nothing more than the annual ‘flu’,” says Dan Chen, chief medical officer of IGM Biosciences and a coronavirus expert by virtue of his PhD thesis.
This will require global governments to follow through on funding promises. The NEJM paper’s authors caution that the Sars and Zika epidemics ended before vaccine development was complete, at which point federal funding dried up and developers were left nursing losses.
Biopharma obviously wants to play its role in the pandemic, but it will be acutely aware that all too often vaccine development represents an economic black hole.
Among these an mRNA vaccine has seized the early lead, courtesy of Moderna, though Johnson & Johnson’s promise to develop an AAV vector-based approach on a non-profit basis might have the most promise. However, despite understandable enthusiasm, the road to having a vaccine approved is long and treacherous.
The need to build sufficient manufacturing infrastructure is just one aspect that will slow the process, and that is before a vaccine with a sufficient efficacy is developed. It could also take a while to find a product with the right mix of safety and ability to generate antibodies that offer sufficient protection.
A recent article by the Coalition for Epidemic Preparedness Innovation (CEPI) in the NEJM pointed to the industry’s ability to respond quickly to the need for pandemic flu vaccines, but said those against Sars had not followed a similar path. Additionally, Covid-19 is an RNA virus, and the industry’s vaccine efforts against this type of pathogen, notably RSV, have underwhelmed.
Early attention
It might surprise that in the coronavirus pandemic Moderna’s mRNA-1273, rather than more traditional vaccine approaches, has seized early attention. One key advantage of RNA (and DNA) vaccines is that they use synthetic processes and do not require culture or fermentation, offering much faster manufacturing.
Moderna itself claims that mRNA vaccines are better at mimicking natural infection, and highlights the “agility” of its manufacturing system. Production for a phase II trial could begin in a few months, and ultimately could allow millions of doses to be made.
Pfizer, which through a deal with Biontech hopes to enter the clinic with another mRNA vaccine this month, told Vantage: “We are working at record pace. While the development process can generally take years, we are working with partners and government agencies to find opportunities to save time wherever we can.”
Unique antigens
Mechanistically, a prophylactic vaccine works by exposing the immune system to antigens unique to the virus in question, seeking to prime the immune system for the quick generation of large amounts of antibodies in the event of an actual infection.
An mRNA vaccine, for instance, comprises mRNA that codes for expression of such a protein antigen. Different vaccines have different properties in terms of whether they generate humoral (B cell and antibody) versus cellular (effector T cell) immunity, and at which sites this is elicited.
Beyond the modality that each vaccine approach uses, and whether adjuvanting is needed to potentiate the immune response, a key consideration is clearly the choice of antigen.
By far the most popular approach has been to target epitopes on Covid-19’s spike protein, a structure found on the surface of the virus. Ideally, antibodies raised against this could bind the virus immediately and stop the infection of host cells. Some vaccines target other so far undisclosed epitopes or proteins.
| Selected vaccines in development for Covid-19 | ||||
|---|---|---|---|---|
| Company/org | Vaccine | Type | Target | Detail |
| Moderna/NIAID | mRNA-1273 | mRNA vaccine | SARS-CoV-2 spike protein | First clinical subjects dosed |
| Cansino Biologics | Ad5-nCoV | AAV5 vaccine | SARS-CoV-2 spike protein | China study under way |
| Shenzhen Genoimmune | LV-SMENP-DC | Synthetic minigene vaccine | Multiple antigens | Clinical trial started Mar 2020 |
| University of Oxford | COV001 | Chimp AAV vaccine | SARS-CoV-2 spike protein | Clinical trial was to have started Mar 2020 |
| Biontech/Pfizer | BNT162 | mRNA vaccine | ? | Clinical trial starting Apr 2020 |
| Inovio | INO-4800 | DNA vaccine | SARS-CoV-2 spike protein | Clinical trial starting Apr 2020 |
| Johnson & Johnson | ? | AAV26 vaccine | ? | Clinical trial starting Sep 2020 |
| Altimmune | AdCOVID | AAV vaccine | SARS-CoV-2 spike protein | Clinical trial starting Q3 2020 |
| Emergent/Vaxart | ? | Undisclosed non-replicating virus | ? | Clinical trial starting H2 2020 |
| Geovax | ? | VLP vaccine | ? | Clinicl trial starting by end 2020 |
| Arcturus | LUNAR-COV19 | mRNA vaccine | ? | Partnership with Duke-NUS Medical School |
| Sanofi | ? | DNA vaccine | Viral surface proteins | Collaboration with BARDA |
| Translate Bio/Sanofi | ? | mRNA vaccine | ? | Deal signed |
| Dynavax/Clover/GSK | COVID-19 S-Trimer | Trimerised fusion protein | SARS-CoV-2 spike protein | Deals signed |
| Greffex | ? | AAV5 vaccine | ? | Preparing for animal testing |
| Akers | ? | ? | Major structural proteins | Licensed candidate from Premas |
| Curevac | ? | mRNA vaccine | ? | Denies that US offered exclusive vaccine deal |
| AJ Vaccines | ? | Protein subunit vaccine | SARS-CoV-2 spike protein | Started precelinical development |
| Heat Biologics | ? | gp96-based vaccine | Multiple antigens/epitopes | Started precelinical development |
| Anges/Takara Bio | ? | DNA vaccine | ? | Collaboration with Osaka University |
| Epivax | ? | Protein subunit vaccine | SARS-CoV-2 spike protein | Collaboration with Uni of Georgia |
| Generex/Epivax | ? | Protein subunit vaccine | Multiple epitopes | To develop Ii-key peptide vaccines |
| Ibio | ? | Protein subunit vaccine | ? | Filed patent |
| Applied DNA/Takis | ? | DNA vaccine | SARS-CoV-2 spike protein | Collaboration to identify candidates |
| Source: WHO list, EvaluatePharma & company statements. | ||||
That would represent an extraordinarily fast turnaround, but even so a vaccine of some sort might be needed even sooner. Thus even a suboptimal vaccine with moderate efficacy that could merely reduce the severity of Covid-19 infection might be a viable way of protecting people as next winter approaches, some think.
“It is hard to imagine fully returning to a pre-Covid-19 life until we have an effective vaccine, most of the population has been infected, or we have therapies that can turn nearly 100% of severe cases into nothing more than the annual ‘flu’,” says Dan Chen, chief medical officer of IGM Biosciences and a coronavirus expert by virtue of his PhD thesis.
This will require global governments to follow through on funding promises. The NEJM paper’s authors caution that the Sars and Zika epidemics ended before vaccine development was complete, at which point federal funding dried up and developers were left nursing losses.
Biopharma obviously wants to play its role in the pandemic, but it will be acutely aware that all too often vaccine development represents an economic black hole.
Traditional and pandemic vaccine development paradigms. Source: CEPI & NEJM.
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