Researchers review the principles of universal vaccine development for key pandemic potential viruses

By Tarun Sai LomteReviewed by Danielle Ellis, B.Sc.Jun 16 2023

A recent review published in Cell Host & Microbe reviewed the efforts to develop universal vaccines for viruses at family and genus levels.

Background

The coronavirus (CoV) disease 2019 (COVID-19) pandemic has led to unprecedented efforts in vaccine research. Despite progress in vaccine development, multiple challenges persist. Moreover, COVID-19 has underscored the lack of a broadly protective universal vaccine that can be effective against several future variants. Research efforts in this direction are underway.

In the present review, researchers discussed the development of broad-spectrum and pan-family and -genus vaccines, focusing on influenza, henipavirus, and CoV. 

Pan-henipavirus vaccines

Henipaviruses fall into two categories – classical and non-classical henipaviruses based on the ability to utilize ephrin as the entry receptor. Animal or human sera after natural infection with Hendra (HeV) or Nipah (NiV) virus can cross-neutralize either virus, laying the foundation for the development of monoclonal antibodies (mAbs) and a pan-henipavirus vaccine.

Whether a vaccine based on HeV or NiV would protect against other classical henipaviruses remains unclear. Vaccine candidates targeting the HeV or NiV glycoprotein have been effective in animal models. HeV soluble glycoprotein (sG)-based protein subunit vaccine, under the trade name Equivac HeV, has been licensed for use in horses.

HeV and NiV sG-based vaccines provided homologous and heterologous protection against both viruses, although the HeV sG-based vaccine was better against NiV. These findings were confirmed in other animal models, and the HeV sG-based vaccine was selected for further development into a pan-henipavirus vaccine.

Equivac HeV’s success as a pan-henipavirus vaccine mainly stems from using the highly conserved glycoprotein and strict receptor utilization, ensuring common neutralization targets. Four NiV vaccines are being developed based on the protein subunit and viral vector platform. Besides, a clinical trial for a messenger ribonucleic acid (mRNA)-based NiV vaccine is underway.

Pan-influenza vaccine

Existing inactivated influenza vaccines (IIVs) target influenza A (IAV) and B (IBV) viruses that cause infections in humans. Although the IIV platform is still widespread and relatively the same after 80 years, the valency of the vaccine has increased over time. IIVs were re-developed based on bivalent, trivalent, and multivalent vaccine formulations.

Genetic and antigenic characterization of circulating seasonal influenza viruses in humans and clinical and epidemiologic data can help determine the need for a vaccine strain update. Many strategies for a universal influenza vaccine are being evaluated in pre-clinical development, focusing on broadly neutralizing antibodies (nAbs) against hemagglutinin.

A 20-mer hemagglutinin mRNA lipid nanoparticle vaccine using all IAV and IBV subtypes was protective in ferrets and mice, with similar breadth across subtypes. There are 800 influenza vaccines currently in clinical trials, including eight multivalent vaccines, per the World Health Organization (WHO).

Pan-CoV vaccine

Severe acute respiratory syndrome (SARS)-CoV, middle-east respiratory syndrome (MERS)-CoV, and SARS-CoV-2 have caused epidemics and pandemics in the past two decades, resulting in unprecedented economic and human loss and global public health disruptions. No anti-CoV vaccine was approved for humans before the COVID-19 pandemic.

Although multiple vaccine candidates were developed for SARS-CoV or MERS-CoV, none received regulatory approval for clinical evaluation. So far, the WHO has granted emergency use listing (EUL) for 11 SARS-CoV-2 vaccines based on whole inactivated virus, mRNA, adenovirus-vectored, and protein subunit platforms.

These first-generation vaccines are based on the ancestral SARS-CoV-2 Wuhan strain and are ineffective against novel immune-evasive variants such as the Omicron variant. Further, immune imprinting effects have been observed with vaccine breakthrough infections with the Omicron variant, wherein cross-reactive ancestral vaccine- or infection-elicited B cells are recalled. Still, de novo Omicron-specific nAbs or B cells are rarely induced.

Thus, second-generation SARS-CoV-2 vaccines have been developed. Moderna and Pfizer have introduced bivalent vaccines based on the ancestral strain and the Omicron variant. Bivalent vaccine-boosted individuals exhibited increased nAb response against Omicron sub-variants. As mentioned, due to immune imprinting, most recalled B cells target ancestral strain epitopes, with relatively fewer Omicron-specific nAbs.

Therefore, research efforts are underway to develop broader third-generation pan-sarbecovirus vaccines. Most pan-sarbecovirus vaccines are under preclinical development. One of the vaccine candidates is based on the mosaic nanoparticle platform containing receptor-binding proteins (RBDs) from SARS-CoV-2 and seven animal CoVs.

This vaccine elicited broad nAb responses in non-human primates and mice. Chimeric mRNA vaccines incorporating RBD, N-terminal domain (NTD), and the S2 domains of the spike protein from SARS-related CoVs have been reported to elicit pan-sarbecovirus immunity. No pan-CoV vaccine has yet been reported.

Conclusion

While there are reports of broad-spectrum nAbs against influenza viruses, CoVs, or henipaviruses, the structural characterization of their corresponding epitopes and, therefore, the vaccines targeting such epitopes are lacking. By contrast, many pan-variant, -sarbecovirus, -beta-CoV mAbs have been identified and characterized. Alternatively, given the ongoing development of pan-genus vaccines, it will be worth considering immunization with neutralizing mAbs as a universal antibody vaccine for early intervention in future outbreaks.