Stanford develops the latest vaccine: 100 times more powerful than mRNA, covering all strains

Maybe humanity can defeat the new crown?

Recently, scientists from Stanford developed a ferritin-based new crown nanoparticle vaccine that can produce powerful, long-lasting, broad-spectrum neutralizing antibodies
in non-human primates.

Experimental results show that the antibody response caused by the new vaccine is 100 times
stronger than that of existing mRNA vaccines.

And more importantly, it can cover all known variants
.

Thesis: https://doi.
org/10.
1101/2022.
12.
25.
521784

If it can be confirmed that it can also produce equally powerful antibodies in the human body, perhaps, the new crown virus will become history
in human society like smallpox.

The vaccine to end the new crown is coming?

Since the outbreak of the pandemic, scientists have come a long way
in vaccine research.

Data shows that in the first year of the pandemic, mass vaccinations averted more than 14 million deaths
.

However, there is still an urgent need for vaccines around the world, with the World Health Organization estimating that nearly 1 billion people worldwide remain unvaccinated against SARS-CoV-2
.
In addition, the cost of vaccines is generally high, and cryogenic storage and transportation have increased its cost, making it unaffordable
for many people.

Moreover, the immunity provided by vaccines through induction or infection weakens over time; At the same time, the new coronavirus is an mRNA single-stranded virus, which is very easy to mutate, thus escaping the protection of
vaccines.

Therefore, there is a great need for a vaccine that provides longer-lasting immunity to all SARS-CoV-2 variants (VOCs) to protect the world's population
, including children and infants.

Now, this good wish is likely to
become a reality.

Researchers from Biohub and Stanford have discovered a ferritin-based protein nanoparticle vaccine, Delta-C70-Ferritin-HexaPro (DCFHP).

They found that when formulated with aluminum hydroxide as the sole adjuvant (DCFHP-alum), the new vaccine elicits neutralizing antibodies against known variants (including Omicron BA.
4/5, BQ.
1, etc.
) and SARS-CoV-1 in nonhuman primates (NHPs) with long-lasting
effects.

In booster immunization one year after primary immunization, DCFHP-alum can also cause a strong antigen response
.

In addition, compared to many new crown vaccines, the storage conditions of this vaccine are not harsh
.
Test results show that DCFHP-alum potency can be maintained at temperatures above standard room temperature for at least 14 days
.

The researchers believe that DCFHP-alum can not only be used as an annual booster shot later, but also safe
for children, including infants.

Why protein nanoparticle vaccines?

Compared with subvaccines, protein nanoparticle vaccines are more easily absorbed by antigen-presenting dendritic cells, and nanoparticles promote the multivalent presentation of antigens, promoting receptor aggregation and subsequent B cell activation
.

At present, this ferritin-based nanoparticle vaccine has shown a strong humoral immune response to SARS-CoV-2 and other viral glycoproteins, and has also a high safety profile
in clinical trials.

Previously, the researchers had tried a protein-based nanoparticle vaccine, S∆C-Fer
.

S∆C-Fer contains a mutated Flintin protease cleavage site and a pre-fusion-stable alternative to 2-proline (2P) (which is also available in FDA-approved SARS-CoV-2 mRNA vaccines).

Importantly, S∆C-Fer also deleted 70 amino acid residues at the C-terminus of the spike ectodomain
.

The spike(s) is a structural glycoprotein expressed on the surface of SARS-CoV-2 and is a key determinant
of viral host and tissue tropism.
SARS-CoV-2 S mediates viral entry into target cells after ACE2 receptor binding and is therefore a potential therapeutic drug target

These residues are deleted and contain immunodominant, linear (nonconformation) epitopes
.
In convalescent plasma, these epitopes are often targeted by antibodies
.

Compared to other vaccines, if these immunodominant linear epitopes are removed from ferritin nanoparticles and the polyvalent presentation of the modified spike protein is greatly improved, the neutralization efficacy
of the induced antibody in mice is greatly improved.

Upgrade S∆C-Fer to DCFHP

In this experiment, the researchers used an upgraded version of the S∆C-Fer,—— Delta-C70-Ferritin-HexaPro, or DCFHP
.

They supplemented the 2P stable alternative with the four proline substitutes described above to create a version
of six proline substitutes (HexaPro).

DCFHP schematic, including modifications made to convert S∆C-Fer to DCFHP

The above work shows that HexaPro SARS-CoV-2 spike protein has higher stability and better expression
than the 2P version.

In addition, DCFHP is more stable than S∆C-FER in the case of temperature changes
.

The experimental results showed that DCFHP-alum elicited a strong and durable immune response
against the SARS-CoV-2 variant in mice.

In addition, by immunizing the mice, the researchers found that DCFHP-alum remained stable
for at least 14 days in the temperature range of 4°C to 37°C.

Therefore, it can be speculated that the DCFHP-alum vaccine does not need to be refrigerated
.

Three-dimensional reconstruction cryo-EM density map of DCFHP

Subsequently, the researchers conducted experiments
in rhesus monkeys.

After two doses of intramuscular immunization of rhesus macaques with DCFHP-alum, long-lasting, powerful neutralizing antibodies, including Omicron BA.
4/5 37 and BQ.
1, were produced, while also producing a balanced Th1 and Th2 immune response
.

Most surprisingly, antibodies to these non-human primate (NHP) also showed strong and durable neutralizing activity
for different SARS-CoV-1 pseudovirus variants.

About 1 year later, the researchers gave rhesus macaques a booster shot with a third dose of DCFHP-alum, which also produced a powerful, broad-spectrum neutralizing antibody response
in them.

In other words, DCFHP-alum can not only act on various variants of the new crown virus, but also promote the vaccination
of the new crown vaccine around the world.

This regimen is very cost-effective and can be
given once a year in the future.

The results of the experiment were pleasantly surprised

To study the stability of the DCFHP-alum vaccine, the researchers stored samples at 4°C, 27°C, or 37°C for different periods of time and evaluated the immunogenicity
of these stored samples in single-dose mouse immunization studies.

Notably, the DCFHP-alum vaccine maintained similar immunogenicity
at all temperatures and storage periods in the pseudovirus neutralization trial.

Therefore, the researchers concluded that DCFHP-alum remained stable
after two weeks of storage at 37°C.

The researchers selected 10 male rhesus macaques between the ages of 3 and 9 and divided them into two groups (A and B).

Both groups of rhesus macaques are first initially immunized simultaneously on day 0, followed by a booster dose (Figure 3A) on day 21 (Group A) or day 92 (Group B).

Based on the assessment of the 14-day booster, rhesus monkeys who received the booster dose later produced better neutralizing antibodies (Figures 3C and D); On average, the neutralization response of group B to different variants increased by about 4 times
relative to group A.

In further studies, it was found that all non-human primates had a neutralizing antibody response to the original strain that lasted at least 250 days (Figures 4A and C).

Similarly, most animals in group B maintained detectable neutralizing potency against BA.
4/5 and SARS-CoV-1 with distinct sequences for a duration of approximately one year (Figure 4D), with titers generally higher than in group A (Figure 4B).

To determine whether DCFHP-alum could be used as an annual vaccine, the researchers gave all rhesus macaques a booster shot on day 381
.

The results showed that rhesus monkeys in both groups A and B showed a strong immune response
.
The mean NT50 values for the original strain, BA.
4/5, SARS-CoV-1 and BQ.
1 were approximately 10^4, 10^3.
5, 10^3 and 10^3, respectively (Figure 5A-H).

To sum up

The researchers said that the DCFHP-alum vaccine, although based on the earliest original strain sequence, can trigger a powerful and broad-spectrum neutralizing antibody response against SARS-CoV-2 variants and SARS-CoV-1 in non-human primates (including against BA.
4/5, BQ.
1 and SARS-CoV-1) and can last for more than 250 days
.

Because DCFHP-alum provides very broad protection against the new crown variant by primary immunization of non-human primates, DCFHP-alom can be used as an important primary vaccine for unvaccinated or uninfected people
.

At the same time, the excellent safety profile of aluminum salt adjuvants as part of routine childhood immunization schedules has been proven over the past decades and is also a commonly used ingredient
in infant vaccines.
Therefore, DCFHP-alum may also be an ideal way
to help establish immune imprinting against SARS-CoV-2 in infants.

In addition, CHO-based cell lines enable low-cost, large-scale production of new vaccines, and can also be stable for more than
two weeks at temperatures above standard room temperature.

Taken together, the researchers believe that DCFHP-ALUM is an excellent candidate
for developing new vaccines.