Protein subunit vaccines: Why they matter now more than ever

On Monday (December 27, 2021), the UAE approved the CNBG Sinopharm's COVID-19 vaccine using the recombinant protein subunit platform. It would be used as a booster for people previously inoculated with two doses of the inactive Sinopharm jab, according to the UAE Ministry of Health and Prevention (MoHAP). Here’s the lowdown on this class of vaccines:

How does a protein subunit vaccine work?

In a nutshell, a protein subunit vaccine harnesses tiny particles containing multiple engineered spikes grown in cell cultures — and then using them as a vaccine to illicit immune response in the recipient’s body. Sinopharm's new recombinant protein vaccine uses the Spike (S) protein that surrounds the SARS-CoV-2 virus. This helps the body identify the virus, then fight it in case of exposure. The technology helps prevent several variants.

It is made typically via recombinant synthesis of protein "antigens" (molecules that elicit immune response), as well as protein isolation and purification methods, Nature explains. "Recombinant" means using genetic engineering to produce the new vaccine. This is done typically by inserting genetic material from the S protein into the genetic material of another organism (yeast, bacterium).

This is achieved by cultivating large amounts of the pathogen (disease-causing agent, i.e. virus/bacteria, in this case SARS-CoV-2). The genetically-engineered organism produces the S-protein, which are then extracted, purified and introduced as the vaccine's active ingredient.

Today, the most familiar example of this vaccine development strategy are the subunit vaccines for influenza.

It is a proven vaccine platform. It is also quite common. Currently, the WHO lists at least about 70 protein subunit vaccine candidates against SARS-CoV-2.

Each one harnesses different immunogen — mainly various forms of the entire Spike (S) protein or its receptor binding domain (RBD), the region of the S protein that mediates viral binding to the ACE2 receptor of target host cells.

Upon binding to the host cell ACE2 receptor the pre-fusion conformation of the S protein undergoes an extended conformational change to a highly stable post-fusion conformation that permits the fusion between the viral particle and host cell membranes.

More immunogenic

Writing for Nature, Nikolaos C. Kyriakidis of One Health Research Group, Universidad de Las Américas (UDLA), Quito, Ecuador, and colleagues explained: "As a general rule, prefusion-stabilised viral glycoproteins are usually more immunogenic, thus being more attractive vaccine targets.”

What vaccines use the protein subunit development platform?

The first forms of developed protein subunit vaccines aimed to harness the ability of protein antigens to elicit immunoglobulins (aka antibodies). In the 1960s, an early example of an “acellular vaccine” was the anthrax protective antigen.

The technique, developed in the 1960s, gained traction in the 1990s with the explosion of genetic engineering, allowing for cloning and ramping up antigen production in vitro (in a test tube, dish, or elsewhere outside a living organism).

This led to the production of large quantities of the hepatitis B surface antigen in yeast cells — a breakthrough that led to the production of the Hepatitis B vaccine.

An “adjuvant” (efficacy/potency booster), is usually added to provoke a robust immune responses.

How many protein subunit-based vaccines had been approved?

The warp-speed COVID vaccine development so far rely on inactivated virus (Sinopharm, Sinovac), nucleic acid (Pfizer, Moderna mRNA) or vector-based strategies (AstraZeneca, Sputnik V). Now, there are at least 10 other PS-based vaccines approved in at least one state/territory:

1. Anhui Zhifei Longcom ZF2001 (approved in [3]: China, Indonesia, Uzbekistan)

2. Novavax NVX-CoV2373 (approved in [30]: Austria, Belgium, Bulgaria, Croatia, Cyprus, Czechia, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Liechtenstein, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, and Sweden)

3. Instituto Finlay de Vacunas Cuba: Soberana Plus (approved in [1]: Cuba)

4. Instituto Finlay de Vacunas Cuba: Soberana 02 (approved in [4]: Cuba, Iran, Nicaragua, Venezuela)

5. Razi Vaccine and Serum Research Institute: Razi Cov Pars (approved in [1]: Iran)

6. Serum Institute of India: COVOVAX / Novavax formulation (approved in [2]: Indonesia, Philippines)

7. FBRI: EpiVacCorona (approved in [2]): Russian Federation, Turkmenistan)

8. Center for Genetic Engineering and Biotechnology (CIGB): CIGB-66 (approved in [4]: Cuba, Nicaragua, Venezuela, VietNam)

9. Vaxine/CinnaGen Co.: COVAX-19 (approved in [1]: Iran)

10. Medigen: MVC-COV1901 (approved in [1]: Taiwan)

What are the advantages of protein subunit vaccine?

Protein sub-unit vaccines offer a number of advantages:

1. Safety:

They are specifically selected for their ability to stimulate immune cells, according to Gavi, the global vaccine alliance. These fragments are incapable of causing disease — as such, subunit vaccines are considered fundamentally safe.

2. Logistics:

Another big advantage is logistics: protein subunit-based vaccines do not need super-cooling, especially compared to mRNA shots.

3. Simplicity:

Rather than injecting a whole pathogen (disease-causing virus/bacteria) to trigger an immune response, PS vaccines — also known as “acellular vaccines” — contain purified pieces of it.

4. Proven platform / production efficiency:

Protein subunit vaccines are already in widespread use (i.e. hep B and acellular pertussis vaccine). In terms of manufacturing, a PS vaccine is based on protein cultivated in factories, which does not require a live (attenuated) or inactivated virus. Attenuated or inactivated vaccines must first grow the virus in huge quantities in stainless steel containers located within in a high bio-safe facility — once grown, they are then attenuated ("defanged”) or “killed” thru UV light or chemical process before placed in vaccine vials.

5. Production:

PS vaccines are far easier to produce compared to attenuated or inactivate virus vaccines, as facilities with high biosafety levels are not required. They must, however, be produced according to Current Good Manufacturing Practice regulations (CGMP). This could potentially change the cost equation as well as distribution.  

6. Affordability:

In theory, it could make COVID vaccines more available to poor countries. Currently, only 6% of the Africa’s 1.216 billion population had been fully vaccinated against COVID-19 so far, the lowest rate among the world’s 7 continents. 

One downside: It frequently raises the necessity to increase booster doses and optimise the “adjuvant" added to achieve stronger and more durable immunisation. 

Is the CNBG recombinant protein subunit (RPS) vaccine the first to be approved in China?

No. Lab trials (on animals) are done first before clinical trials (test on humans). On April 10, 2021, CNBG obtained regulatory approval for human testing stage in China for its PS vaccine.

A month earlier, on March 17, 2021, the Chinese Academy of Sciences Institute of Microbiology’s recombinant protein subunit vaccine against COVID-19 was approved by the Beijing government for emergency use. It was developed by the institute and Anhui Zhifei Longcom Biopharmaceutical, and is the first vaccine using the RPS technique approved by the country for emergency use against COVID-19.

Sinopharm’s BBIBP-CorV (Vero Cells), on the other hand, has been approved in 80 countries (including the UAE); Sinopharms’ (Wuhan) Inactivated (Vero Cells) vaccine has been approved in 2 countries — China and the Philippines.