Antibody production rate up to 97%! Is the HIV vaccine coming?

As we all know, the terrible thing about HIV compared to other viruses is that it can directly attack the human immune system, when the body's immune system gradually collapses, it is also the onset of AIDS patients, at this time, the human body in addition to the attack of HIV, but also to face other viruses and bacteria that take advantage of the void, the patient's life is usually at the end
of this period.

To make matters worse, nearly four decades after scientists isolated HIV, there is still no effective AIDS vaccine
.
This is because HIV belongs to the reverse transcription RNA virus, itself has a high gene mutation rate, secondly, when replicating in the host cell, the RNA needs to be reverse-transcribed into DNA, and the reverse transcription process error rate is very high, which makes the shell (membrane protein) of the HIV virus also easy to mutate, and even the early and late viruses in the same patient are different, because the antibodies produced by the vaccine are invalid
。 In addition, the specific spike membrane protein in the outer layer of the HIV virus has a high degree of glycosylation, which is equivalent to putting another layer of "sugar shield" on the HIV antigen, which can escape the recognition and attack
of human immune cells.
In addition, the HIV virus can lurk inside cells and complete infection "without leaving home" through cell-to-cell contact, which makes antibodies useless at all
.
The lack of suitable animal models is also one of
the reasons why vaccines are difficult to develop.

However, studies have found that a small percentage of people living with HIV in the world develop a broadly neutralizing antibody (bnAbs)
against HIV.
This antibody not only fights the HIV strain present in their body, but also has an effect on other HIV subtypes circulating around the world, which is equivalent to a "master key"
against HIV.
But the production of such antibodies is extremely difficult
.

To this end, scientists hope to find a vaccine that can induce the production
of bnAbs in humans.
At present, there are three main strategies for inducing bnAbs in this field, including: (1) B-cell lineage vaccine design, that is, is, isolation of bnAbs from natural HIV-infected patients, and then using the computational derived clonal lineage as a template to design HIV vaccine immunogens; (2) Germline targeted vaccine design, first stimulating bnAbs precursor B cells, and then using a series of reasonably designed enhanced immunogens to guide B cells to mature from the original naïve B cell (or germline) state, thereby inducing bnAbs production; (3) Epitope-centered vaccine design, that is, the use of genetic engineering means to synthesize the epitope of HIV virus (chemical groups that can determine antigen specificity, also known as antigen determinants) in vitro, and directly use
it as a vaccine.

Regardless of the strategy, the key to inducing bnAbs is how to stimulate the rare B cell precursors that can produce bnAbs with vaccines, that is, whether the most promising "elite force" can be selected from immature naïve B cells for further development
.
This step is similar to a "start-up" stage, and the difficulty is that this batch of "elite troops" only accounts for one millionth of the total number of B cells!

The importance of the "initiation" phase is most evident
in germline targeted vaccine design strategies.
After the "start-up" is completed, the use of immunogens that are more and more similar to natural glycoproteins is gradually strengthened, guiding B cells to undergo somatic supermutations, and bnAbs will also become extremely antigen-friendly in this process, and finally achieve effective resistance to the invading HIV virus
.

On December 2, in a Science article "Vaccination induces HIV broadly neutralizing antibody precursors in humans," researchers verified the safety and feasibility of germline targeted vaccine design strategies, showing that 35 of the 36 people who received two doses of the vaccine developed antibodies without serious side effects
。

Figure 1 Research results (Source: [1])

The researchers recruited a total of 48 healthy participants, of whom 18 received two doses of the low-dose vaccine, 18 received two high-dose doses of the vaccine, and the remaining 12 received two doses of placebo with an eight-week
interval between the two doses.
The vaccine is designed to activate the B-cell precursor of HIV VRC01 class bnAbs, a broad-spectrum neutralizing antibody
to HIV that has been studied so far.
The researchers collected memory B cells and plasma blasts from participants' peripheral blood mononuclear cells, as well as GC (germinal centers) B cells
obtained by lymph node puncture, multiple times in the 20 weeks before and after the participants' vaccination/placebo 。 Through epitope-specific B-cell sorting, B-cell receptor sequencing, and bioinformatics statistical analysis, the researchers found that: ■ Of the 36 people who received the vaccine, 97% developed VRC01 bnAbs at the end of the study; ■ Participants who received high-dose vaccines had slightly higher antibody levels compared to participants who received low-dose vaccines; ■ Of all 48 participants, 98 percent experienced mild side effects, most of which disappeared within 1-2 days, consistent with
other vaccines.

Fig.
2 Presence of VRC01 IgG B cells in blood and lymph nodes (Source: [1])

Commenting on the results, Gary Kobinger, an associate professor in the Department of Microbiology and Immunology at the University of Texas, said: "This paper describes the best B-cell immune response
to HIV vaccination I have ever seen.
However, depending on the level of antibodies produced, Kobinger predicts that more than two injections may be needed to prevent infection
.

Kobinger also has great expectations for this vaccine design strategy, which can also be applied to the development of vaccines for other rapidly mutating viruses: "If it succeeds, it will become a new tool
in the arsenal of vaccinologists against viruses with high mutation rates.
" ”

In addition, in January this year, Moderna and the International AIDS Vaccine Initiative announced that they had begun human trials of an mRNA AIDS vaccine, with Phase 1 clinical trials expected to be completed
in 2023.
The results of the Phase III clinical trial of Johnson & Johnson's compound vaccine in collaboration with Harvard University are expected to be released
in 2022/2023.
The Chinese Center for Disease Control and Prevention and the National Institute of Allergy and Infectious Diseases of the United States also signed a memorandum of cooperation to carry out joint clinical trials
of HIV vaccines between China and the United States based on the good complementarity of the vaccines developed by the two sides.
I believe that with the efforts of scientists at home and abroad, a safe and effective AIDS vaccine is not far from us in the future!