Recently, everyone has noticed that a new member has been added to the lineup of my country's new crown vaccine approved for emergency use - genetically recombinant subunit vaccine. This type of vaccine is different from the previously approved inactivated vaccine and adenovirus vector vaccine. One of the most concerning differences is that this vaccine requires 3 injections at an interval of 6 months to complete the vaccination process. .
First, let’s understand what subunit vaccine is. The inactivated and attenuated vaccines we mentioned before, antigen are composed of complete pathogens. Subunit vaccines, on the other hand, contain only certain components derived from disease-causing bacteria or viruses. These ingredients are highly purified proteins or synthetic peptides, which are the main substances that cause the body's immune response. In other words, subunit vaccines are not complete pathogens, so they inherently do not have the ability to infect the human body and cause disease.
So, how are subunit vaccines developed? Is the effect good or not? Let’s start with a disease that is almost a household name in China—hepatitis B.
Unexplained jaundice hepatitis
Hepatitis B virus is almost the most common viral disease in the world and is the main cause of jaundice.
There is evidence that the virus was transmitted through injection and other means as early as the late 19th century. At that time, there was an incident where more than 15% of people developed jaundice after vaccination because smallpox vaccine was contaminated with blood products.
During World War II, the United States prepared to launch a military attack on German-occupied North Africa in 1942. In order to prevent troops from being infected with yellow fever in Africa, soldiers in the Allied forces were vaccinated against yellow fever on a large scale. Because some of the vaccines were contaminated with plasma containing hepatitis virus , more than 28,000 soldiers eventually contracted jaundice hepatitis , and 62 died.
More than 40 years after the outbreak, when scientists took out blood samples from and during World War II and conducted retrospective serological analysis, they found that 97% of the vaccinees who had received serum-contaminated vaccines during World War II were infected. Hepatitis B virus.
Of course, during World War II, people still knew nothing about the hepatitis B virus.
Hepatitis B virus discovered by accident
Although hepatitis B virus had caused outbreaks and epidemics before it was identified and discovered, what is surprising is that the discovery of hepatitis B virus was not the result of scientists’ tireless search, but the result of a search for basically unknown viruses. Research in related basic science fields.
In 1964, American scientist Baruch Samuel Bloomberg discovered an antigen-antibody interaction between the serum of a transfused hemophilia patient in New York and the serum of Australian Aboriginals. So this reactant protein was originally named "Australian antigen".
At the time, it was not clear what this antigen actually represented. Bloomberg found that the "Australian antigen" is rarely found in healthy Americans, but it is very common in patients with leukemia , so it is suspected that there is some connection between leukemia and this antigen.
However, a series of subsequent observations found that since leukemia patients often require blood transfusions, it seems that the "Australian antigen" has a closer relationship with hepatitis. Epidemiological survey found that hepatitis often occurs in leukemia patients who frequently receive blood transfusions, and the "Australian antigen" is more common in these people.
Blumberg's most compelling observations came from studies of patients with Down syndrome in whom the Australian antigen was not found on initial presentation but was found on subsequent tests. In other words, the emergence of "Australian antigen" and the onset of hepatitis almost appear together.
Then, Bloomberg raised another question: Is "Australian antigen" positivity more common in patients with hepatitis? He demonstrated through scientific hypothesis testing that the "Australian antigen" was indeed found to be more common in people with hepatitis.
Next, Bloomberg wanted to see whether this "Australian antigen" was the virus itself? Or is it just a component produced by the virus. Finally, it was confirmed through electron microscopy , animal transmission studies and other studies that the "Australian antigen" is a component of the hepatitis virus. The "Australian antigen" was later called HBsAg (hepatitis B virus surface antigen).
From the entire process of discovering the hepatitis B virus, we can see that although it was an accidental discovery, Bloomberg showed the curiosity and extremely rigorous scientific thinking of an outstanding scientist.. Bloomberg also won the 1976 Nobel Prize in Medicine or Physiology.
The earliest subunit vaccine
A unique feature of hepatitis B virus is that when observed under an electron microscope, in addition to the entire virus particles, a very large number of spherical and rod-shaped particles containing only HBsAg are also found in the peripheral blood of virus carriers. In some carriers, these particles account for more than 1% of their total serum protein. This discovery formed the basis for creating the hepatitis B vaccine .
Hepatitis B virus under an electron microscope, and non-infectious S protein particles
In 1969, Bloomberg and Millman tried to prepare a hepatitis vaccine from blood containing the "Australian antigen". This vaccine required particles containing HBsAg, but Contains no nucleic acid and essentially no infectious particles.
However, the procedures to remove impurities including infectious components are very complex and include centrifugation, enzymatic digestion, column gel filtration, differential density centrifugation in sucrose solutions, dialysis, differential density in cesium chloride solutions Multiple steps such as centrifugation and dialysis.
At that time, the production technology was not enough to produce a qualified hepatitis B vaccine, and it was not until more than 10 years later that mass production was achieved.
Blumberg received the 1976 Nobel Prize in Medicine or Physiology for his work on the "Australian Antigen"
A convincing vaccine trial
By the early 1980s, Wolf Smunis and colleagues completed conducted a series of vaccine field trials.
The first challenge in a vaccine trial is selecting a study population with a high enough risk of infection to make a vaccine trial feasible. At the same time, Smuniz believes the trial should be conducted among people who could benefit from a potentially effective vaccine.
Smunis found that the risk of hepatitis B infection is high among gay men in New York City. Among the more than 10,000 men surveyed, the hepatitis B virus infection rate was 68%, and the estimated annual new infection rate is 19.2% to 30%. . This population was ultimately selected as the first group of field trial subjects.
The study included 1,083 male subjects between November 1978 and October 1979. 549 people received the vaccine and 534 received a placebo. The vaccine is administered in three doses: the first two 1 month apart, and the third 6 months apart. A total of 93% of subjects received all three vaccinations.
The research results convinced everyone.
First of all, there is no question about the safety of the vaccine. There were no differences in the frequency or severity of adverse events between the vaccine and placebo groups.
Secondly, the antibody response in the vaccinated group was satisfactory. Within 2 months after the first vaccination, 77% of vaccine recipients developed protective antibodies (hepatitis B surface antibodies), increasing to 96% after the third vaccination. Among placebo recipients, only 2–5% developed surface antibodies.
Third, there was a clear difference in the number of HBV infections between vaccine and placebo recipients. Among the 122 people found to be infected (including subclinical infection ), 93 cases (76.2%) were from placebo recipients, while only 29 cases (23.8%) were from vaccine recipients, with a statistically significant difference ( p 0.0001).
This important randomized, double-blind clinical trial demonstrated the effectiveness of the hepatitis B vaccine, a conclusion that was subsequently replicated by multiple trials in different risk groups and geographical settings, with consistent results.
The Smunis experiment was not only successful, but also very efficient.Compared with the 1 million children who participated in the Salk polio vaccine that year, the number of participants in this study was just over 1,000.
Two concerns about blood-borne vaccines
Within two years of the publication of this successful pivotal trial, the US FDA approved a blood-borne HBV vaccine.
The earliest vaccines were produced by collecting HBsAg (22 nm particles) from the plasma of people with chronic hepatitis B virus infection. Maurice Hilleman, an American microbiologist at Merck , used three serum treatments ( pepsin , urea and formaldehyde ) as well as stringent filtration to ensure that those with the infection were removed substances to produce products that can be used as safe vaccines.
Ultimately, millions of doses of the plasma-derived hepatitis B vaccine were used worldwide.
Although the blood-borne hepatitis B vaccine was very successful and no clear safety issues arose, due to the global HIV epidemic in the 1980s, scientists still had some concerns about the safety of the blood-borne vaccine, and the need to manufacture the vaccine Isolating it from the plasma of infected people is also a problem for further expansion of production.
This problem prompted the birth of the first genetically recombinant vaccine in human history.
Gene recombination technology provides unlimited potential for vaccine production
htmlIn the 1980s, scientists tried to use gene recombination technology to enable the subunit of the hepatitis B vaccine, HBsAg, to be expressed in other organisms. This technology freed vaccine production from the need for human plasma. limitations, offering the potential for almost unlimited vaccine production.
In other words, scientists replaced the HBsAg isolated from the plasma of infected people with synthetic HBsAg.
Most of the currently approved genetically recombinant hepatitis B vaccines are composed of the 226 amino acid S gene product (HBsAg protein). The vaccine produced by
yeast is the most widely used vaccine. It is made by expressing the HBsAg protein in genetically engineered yeast cells containing the S gene ( Saccharomyces cerevisiae or Hansenula yeast). The expression plasmid only produces HBsAg protein in yeast cells and does not contain the actual virus.
The genetically recombinant hepatitis B vaccine only contains the S antigen protein
The polypeptide expressing HBsAg in this genetically recombinant hepatitis B vaccine automatically assembles into 22nm spherical particles, similar to the complex and sustained isolation in the serum of patients with chronic hepatitis B virus infection. HBsAg particles. This artificial HBsAg particle also contains antigenic determinants that play an important role in the immune response to .
After the success of the genetically recombinant hepatitis B vaccine, the world's most widely used vaccine
, scientists have seen hope of controlling the spread of hepatitis B around the world.
The International Conference on Prospects for the Elimination of Hepatitis B, held in February 1990, explored the possibilities for controlling and eradicating the disease. In 1992, World Health Organization (WHO) included genetically recombinant hepatitis B vaccine in the expanded vaccination plan. In 1997, WHO recommended that all countries include hepatitis B vaccine in the national planned immunization system. By 2004, 129 countries had implemented such programs. The hepatitis B vaccine is now one of the most widely used vaccines in the world.
According to the "2019 World Health Statistical Yearbook" released by the WHO, the application of hepatitis B vaccine worldwide has significantly reduced the incidence of chronic hepatitis B. In the pre-vaccine era, the prevalence of hepatitis B in children under 5 years old was 4.7%. By 2017 This number has dropped to 0.8% this year.
It has played a decisive role in the prevention and control of hepatitis B in my country.
From the perspective of China, vaccines have also achieved significant results in the control of hepatitis B.
The World Health Organization defines countries or regions with a hepatitis B virus infection rate of more than 8% as high-endemic areas, countries or regions with an infection rate of less than 2% as low-endemic areas, and countries or regions with an infection rate of 2% to 8%. Defined as a moderately endemic area.
Since the Ministry of Health of my country included hepatitis B vaccine in planned immunization management in 1992, the positive rate of hepatitis B surface antigen in my country's general population dropped from 9.75% in 1992 to 7.18% in 2006, and then dropped to about 5% in 2020. my country has dropped from a high prevalence area of hepatitis B to the level of a moderately endemic area.
The number of hepatitis B virus carriers in my country dropped from 120 million in 1992 to 93 million in 2006, and to 70 million in 2020. The prevalence of hepatitis B has declined year after year.
The contribution of the hepatitis B vaccine is even more prominent at the source of children's prevention. In fact, in 2006, the hepatitis B virus carrying rate among children under 5 years old in my country reached 0.96%, less than 1%. By 2014, this figure had dropped to 0.32%, achieving the World Health Organization Western Pacific Region hepatitis B control goal Target.
In 2014, the World Health Organization awarded China an award for its efforts in promoting hepatitis B vaccine and controlling the spread of hepatitis B virus. Some foreign experts believe: "This result is one of the greatest achievements of global public health in the 21st century."
At present, in my country's planned immunization program, hepatitis B vaccine and BCG vaccine are the first to be vaccinated for every healthy baby. vaccine.
The existing vaccines are not perfect, but they are good enough.
The recombinant hepatitis B vaccine is certainly not perfect. It must be judged from a harsh perspective and has its shortcomings. The most prominent point is that the immunogenicity of and is not strong enough. This is reflected in the fact that a small number of vaccinated people are unable to produce protective antibodies after vaccination and need to be re-vaccinated.
In this regard, scientists have also developed the recombinant vaccine containing the pre-S region gene, which has been proven to produce better protection. However, because the manufacturing cost is significantly higher than existing vaccines, it is not widely used. The World Health Organization and health departments of various countries also believe that the existing recombinant hepatitis B vaccines are good enough, and there are currently no plans to completely replace them with new vaccines.
The recombinant subunit COVID-19 vaccine is worth looking forward to.
That’s it for the story about the hepatitis B vaccine. It can be seen that as a representative of the recombinant subunit vaccine, the recombinant hepatitis B vaccine has the advantages of high yield, high safety, easy storage and transportation, etc. And it was a huge success.
The recombinant subunit vaccine for the new coronavirus developed using the same technical route should also have similar advantages.
Of course, people will ask why the recombinant subunit COVID-19 vaccine requires 3 injections, and there is a 6-month interval between the first and third injections? This can be said to be the norm for this type of vaccine. Our current vaccination schedule for hepatitis B vaccine also requires three injections (0-1-6 months).
And clinical research data also shows that after 2 doses of the recombinant subunit COVID-19 vaccine, 76% can produce neutralizing antibodies ; after 3 doses, 97% can produce neutralizing antibodies, and the antibody level is relatively high. It can reach twice the amount of serum antibody in recovered patients.
It can be seen that the recombinant subunit COVID-19 vaccine has shown good potential in clinical research. In the vaccination of a wider range of people, it is also worth looking forward to whether it can stand out among the many new coronavirus vaccine technical routes.
Time waits for no one to get the COVID-19 vaccine.
Of course, as we said before, the vaccines developed through each technical route have their advantages and disadvantages. At this stage, there is no need to wait for the perfect vaccine before getting vaccinated. From the evolutionary history of the hepatitis B vaccine, we can find that vaccine development is constantly evolving and improving. A more perfect vaccine may always be the next one, but the reality cannot allow us to wait any longer.
Research shows that the currently approved COVID-19 vaccines are safe and effective, and vaccination can produce good protective effects. Only when everyone is vaccinated can it be possible to establish herd immunity as soon as possible and end this unprecedented new coronavirus pandemic worldwide.
References
1.Blumberg B. (2010) Hepatitis B In:Artenstein A(ed) Vaccines: A Biography. Springer, New York
2.Damme P. et al (2018) Hepatitis B Vaccines In:Plotkin's Vaccines (7th ed) Elsevier , PA. USA
3. Hilleman M. (2011) Three Decades of Hepatitis Vaccinology in Historic Perspective. A Paradigm of Successful Pursuits In: Plotkin S. (ed) History of Vaccine Development. Springer , New York
