New Improvement in Universal Vaccines and Long-acting Neutralizing Antibodies

COVID-19 has spread rapidly since the winter of 2019, and even today, the whole world is still shrouded in its haze. Simultaneously, rapid progress has also been made in the R&D of drugs and vaccines for COVID-19 in the biomedical industry. Vaccines, as the first line of defense against the pandemic, have acted as an important role. So far, 7 vaccines have been approved for marketing in China. The all-course vaccination rate of COVID-19 vaccines in China is above 87%.

However, COVID-19 vaccines have been developed by scientists in a short term and vaccinated on a large scale, but the SARS-CoV-2 is getting more virulent from the original strain to Delta strain, and to the popular Omicron strain recently.

In terms of mRNA vaccines, adenovirus vector vaccines or inactivated vaccines, the vaccine defense line built by human beings seems to be inadequate in the face of Omicron strain. Studies have proved that after three doses of Sinovac vaccines, compared with the neutralizing antibody against the original virus, the titer of that against Delta and Omicron mutants have decreased by 3.3 times and 16.5 times respectively. The effectiveness has decreased to 45.7% in 10 weeks after vaccinating three doses of Pfizer mRNA vaccine, which is greatly reduced compared with the original virus strain (the effective rate of the original strain is 90%).

Responding to the mutating SARS-CoV-2, vaccine companies are updating their own vaccines continuously. Whether there is a universal vaccine with wide protection to prevent all mutants of SARS-CoV-2?

Universal vaccines come as expected.

Prior to answering this question, we'd like to take a macro view of SARS-CoV-2. Coronaviruses can be divided into two subfamilies, including Letovirinae and ortho-coronavirus. The latter can be further divided into four genera: α, β, γ and δ. SARS virus (SARS-CoV) and novel coronavirus (SARS-CoV-2) are β genus of the aforesaid subfamily.

Different technical paths, including recombinant protein, DNA and mRNA, may be adopted to the universal coronavirus vaccine. At present, the most remarkable research progress of universal coronavirus vaccine is still in early clinical stages.

A paper published in Science in 2021 proved that researchers used a vaccine platform called mosaic nanoparticles to generate four different nanoparticle vaccines. One vaccine only presented RBD (receptor binding domain) of SARS-CoV-2, and the other three vaccines could present RBD of four or eight different coronaviruses.

After injecting these vaccines into mice, the researchers found that a wide range of neutralizing antibody immune responses could be activated. The activated neutralizing antibody can not only identify and neutralize SARS-CoV-2, but also recognize and neutralize RBD of coronavirus strain which is not present in the nano-vaccines.

VBI Vaccines has rolled out a vaccine under research that concurrently presents the spike proteins of SARS-CoV, MERS-CoV and SARS-CoV2 by using this technology platform. In the animal test, this pancoronavirus candidate vaccine, named as VBI-2901, can not only increase the titer of neutralizing antibodies against the original COVID-19 strains, Beta variants, Delta and Omicron strains by 2-5 times, but also stimulate the antibody responses against SARS-CoV and MERS-CoV. The produced antibodies also can recognize the HCoV-OC43 strains not presented in the vaccine that cause seasonal flu. At present, the company is still optimizing this candidate vaccine.

In China, taking Recbio as an example, its vaccine ReCOV is not targeted for Omicron, but it has the possibility of "broad spectrum" and has good cross-immunity and immune persistence for major pandemic strains, including Omicron, in accordance with the clinical data disclosed by the company. It can be accounted to the targets of RBD and NTD, which contain multiple conservative epitopes.

According to the researchers, it will not be as difficult as that against HIV or influenza to find a vaccine with broad protection against coronavirus.

It depends on long-acting neutralizing antibody to fight against COVID-19.

Vaccination can remarkably reduce the risk of severe illness and mortality, but there are still some special groups that cannot be vaccinated or have poor response to vaccines. Therefore, it is difficult to produce the protective effect after vaccination. About 2% of the global population is currently at high risk of under-responding to COVID-19 vaccines, including cancer patients undergoing chemotherapy, hemodialysis patients, patients taking drugs after organ transplantation or patients taking immunosuppressive drugs to treat diseases such as multiple sclerosis and rheumatoid arthritis. It is a better choice for special groups to be vaccinated with long-acting neutralizing antibody.

Spike protein (Spike) is the key structural domain to bind to host cells in the structure of SARS-CoV-2, and the binding of mediating receptor and membrane fusion is of vital significance to determine the infectivity and transmission ability of the host. Coronavirus spike protein can be divided into two structural domains, i.e. S1 and S2 in terms of functions. The former is responsible for receptor binding and the latter is responsible for cell membrane fusion. S1 subunit also contains RBD.

There are five steps for SARS-CoV-2 infecting human cells, including: adsorption, releasing genetic material, replication and proliferation, assembling and releasing virions. The first and crux of the aforesaid steps is the adsorption of human cells. Therefore, in order to effectively prevent SARS-CoV-2 infection of human cells, efforts should be made to block the binding of SARS-CoV-2 Spike protein with ACE2 receptors. The monoclonal neutralizing antibody targeting Spike protein in SARS-CoV-2 came into being with the guidance of this idea.

So far, a total of five neutralizing antibodies have been approved by FDA, three of which have been discontinued, including Sotrovimab of GSK/Vir Bio, REGEN-COV of Regeneron and Bamlanivimab/Etesevimab of Eli Lilly/Junshi. Only Evusheld of AstraZeneca and Bebtelovimab of Lilly are available at present. Facing the constant shock of mutant strains, COVID-19 neutralizing antibody is quietly exiting with its reduced efficacy.

Evusheld of AstraZeneca is a combination of two monoclonal antibodies, namely tixagevimab and cilgavimab. In June 2020, AstraZeneca obtained the authorization of Evusheld from Vanderbilt University Medical Center because it can prolong the half-life through optimization and reduce the binding of Fc receptor and complement C1q. Compared with traditional antibodies, the prolonged half-life has tripled the persistence. The half-life of Evusheld in human body lasts about 90 days after modification.

Available data show that Evusheld has good pre-exposure prophylaxis effect for the SARS-CoV-2 variants prevalent during the study period. The duration is 6 months. The study is still ongoing, in a bid to obtain more data to determine the exact duration of preventive protection. Besides, in vivo data of mice infected with Omicron BA.1, BA.1.1 and BA.2 proved that Evusheld can remarkably reduce the viral load and lung inflammation caused by three sub-strains. SARS-CoV-2 load is positively correlated with the increase of disease severity, mortality and COVID-19 sequelae.

Evusheld has been approved by FDA and EMA for its pre-exposure prophylaxis against COVID-19. Applicable people encompass those who have moderately to severely impaired immunity due to medical reasons, or who cannot produce a sufficient immune response to COVID-19 vaccines because of immunosuppressive drugs or treatment; as well as those who are not recommended for injecting approved or authorized COVID-19 vaccines due to a history of serious adverse reactions (such as severe allergic reactions) to COVID-19 vaccines and/or COVID-19 vaccine ingredients.

The optimized neutralizing antibody of COVID-19 can not only significantly prolong the half-life, but also possesses the ability of the potent treatment and preventing COVID-19 infection in a long term.

At present, many public health researchers are looking for and studying influenza vaccine models to guide how to respond to the lasting threat of SARS-CoV-2, which may indicate an annual vaccination in the future for the prevention of COVID-19 infection, just like the same measures against seasonal flu. For people who cannot be vaccinated or have poor response to vaccines, a long-acting neutralizing antibody will be a great addition.

Reference:

1.     Coronavirus (COVID-19) Update: FDA Authorizes New Monoclonal Antibody for Treatment of COVID-19 that Retains Activity Against Omicron Variant；

2.     Moderna announces clinical update on bivalent COVID-19 booster platform；

3.     Taylor PC, Adams AC, Hufford MM, et al. Neutralizing monoclonal antibodies for treatment of COVID-19. Nat Rev Immunol. 2021;21(6):382-393. doi:10.1038/s41577-021-00542-x.