OCD style is too long to look at the version:
- 1. The current ability of the new crown vaccine to prevent infection is very poor;
- 2. Vaccination or infection may be re-infected;
- 3 variants will make vaccines worse and worse;
- 4 Repeated vaccination does not solve the problem;
- 5 Physical protection measures will still be effective;
- 6 Vaccines still have a reliable effect;
- 7 new vaccines and antibodies on the way.
Abstract: The effect on preventing "infection" is not good, the proportion of IgG4 is increasing, the original sin of antigen has been basically proven, and the contradiction between natural variation and immune stress screening has never disappeared... Despite all the "negative" problems of the new crown vaccine, do we still need to get the new crown vaccine? What should the future of COVID vaccines look like? What do we have besides vaccines?
This is a big topic, before writing I also thought of a few versions or exciting or depressing opening mode, helplessly I don't have the sensational ability of the "Wandering Earth" crew, so I opened with a seat of nonsense plainly, I hope everyone can also read this article plainly, without emotional color.
Image purchased from: DepositPhotos
Next, there is a lot of negative information related to the new crown vaccine, which we must face whether we accept it or not.
1
Prevention of "infection" is not effective
The most useful sentence for denying the effectiveness of the new crown vaccine is "if the vaccine is really useful, how can so many people still be infected".
Although this statement completely dismisses the effectiveness of symptomatic infection, especially in preventing hospitalizations, severe cases, and deaths, it cannot be denied that an ideal vaccine should provide both "protection against morbidity" and "protection against infection".
Confidence in vaccines should first come from foreign vaccine research based on mRNA platforms, as well as some domestic "over-descriptions" of inactivated vaccines.
The effectiveness (protective efficacy) of early messenger ribonucleic acid (mRNA) vaccines against "infection" is as high as 95%, while the protective efficacy of other overseas vaccines is 66.5% (Ad26 adenovirus), 72.3 (ChAd-Y25 adenovirus), and 80.6% (inactivated - India) [1]; The effectiveness of inactivated vaccines in China was described as "no infection" in the early news, and the subsequent phase III clinical study also broke this statement [2,3].
Source: Reference 1
All these have led to people's expectations for the effectiveness of various new crown vaccines in preventing "infection".
But what about the facts? The relevant data, including 95%, are actually the overall effectiveness (VEsym) of the new crown vaccine for including "symptomatic infection" or "asymptomatic infection", while domestic vaccines have used VEsym as an effectiveness indicator in phase III clinical studies, but most R&D units have published research results that meet the requirements of 50% of the World Health Organization (regardless of homologous vaccination or heterologous booster) [4-8].
For "asymptomatic infection", the effectiveness against asymptomatic infection (VEasym) was given only on the basis of Ad26 and ChAd-Y25 in the early stage, which was 14.6 percent (95% CI, -12.1 to 34.9) and 65.5 percent (95% CI, 39.9 to 81.1) [9,10], respectively, and then randomized controlled studies or cohort studies during the epidemic of different strains confirmed the effect of different new coronavirus vaccines against "asymptomatic infection" after receiving a single dose of mRNA vaccine at different times VE ranges from 36 to 79 percent [11], and mRNA vaccines are even thought to be up to 90 percent effective against asymptomatic infections for up to seven months [12].
From the data, persistence is ideal, isn't it?
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However, all this only predates the emergence of the Omicron (ο) variant.
When Omicron hits, the reality that various new crown vaccines must face is that "any infection", including "symptomatic infection" and "asymptomatic infection", will be greatly reduced - not only to face the challenge of reducing the short-term effectiveness of preventing infection, but also to accept the reality that the effectiveness of infection will continue to decline over time.
Effectiveness of different coronavirus vaccines during the Omicron period [13,14]
However, thanks to the new coronavirus, we have left a way to live: both immunization and "hybrid immunity" with both immunity and infection provide a highly effective and relatively slow decay of effectiveness in preventing severe disease – although the risk of breakthrough infection and reinfection remains.
Perhaps in the future, everyone will inevitably be infected with – or even reinfected – with the new coronavirus, and the role of vaccines can only be secondary, focusing and positioning on providing high efficacy against severe disease and death.
2
The risk of reinfection cannot be ignored
When the vaccine has been difficult to resist the "infection", then we have to accept the results of being infected by the new crown virus, and then we will hear two very strong voices:
1. After the yang, there will be no more yang.
2. After being infected with the new coronavirus once, the symptoms become milder and milder.
In fact, the first statement has been rejected as early as 2020, when 16.04% of patients who first found that nucleic acid had "turned negative" had "Fuyang" [15], and then a retrospective study in 2021 also found that "Fuyang" was not a case [16].
Of course, "Fuyang" does not prove that it is re-infected with the new coronavirus [17], and after the release of relevant studies, the domestic health department also quickly responded to such phenomena, saying that the risk of infection in Fuyang people is very low, but it is still contagious.
When we breathed a sigh of relief because the risk of "revival" was not high, and we did not find that we would be infected with the new coronavirus twice, the world's first case of "reinfection" raised people's hearts to their throats and eyes - which means that it is less and less likely to shape a "herd immunity" barrier through infection alone.
At first, many people idealized that the herd immunity shaped by "immunization" could be shaped by the new crown vaccine, but it was broken by the new crown virus; Others believe that herd immunity based on "infection" is indestructible, just like chickenpox or measles, which can be infected once and can be immune for life, but it is also shattered by reality.
An article published in The Lancet in October 2020 mentioned that an American man was infected with the new coronavirus twice in April and May, which was also the first officially recorded "reinfection" case in the world; Not only that, but the man's symptoms were even more severe after "reinfection" than the first infection [18].
Disease characteristics of "reinfection" cases[19]
After that, the story became logical, and cases of "reinfection" were reported in Hong Kong SAR, Belgium, Ecuador and other places [19]. Subsequent studies have found that "reinfection" may occur not only within one month of the first infection, but also six months after the first infection, but at a relatively low rate [20-24].
In terms of severity, there is growing evidence that the severity of "reinfection" in the population is milder than that of the first infection [25-27], but this does not mean that "reinfection" is not risky.
A US study of veterans found that "reinfection" was also associated with a risk of serious complications [28] and a significantly higher risk of complications compared with "patients who did not reinfect" or "patients who developed reinfection but did not need to see a doctor" (many misinterpreted the study to mean that reinfection was at a higher risk than the first infection).
In addition, some results suggest that people with comorbidities are more likely to have severe "reinfection" than healthy adults without comorbidities [29-31], so for people with comorbidities, even if they have been infected with the new coronavirus, there is also a risk of reinfection or even severe infection.
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What about the "heterozygous immunity" formed by both being fully vaccinated and infected?
The immunity given by the vaccine is not enough to resist the reinfection of the virus, the immunity of natural infection is not enough, and there is also a risk of disease, can the combination of the two "heterozygous immunity" bring reliable protection?
Image from [32]
In an article published on the preprint website medRxiv[32], as of November 9, 2022, about 94% of people in the United States have been infected with the new coronavirus at least once, and 91.8% of people are still "re-infected" after vaccination, that is, "heterozygous immunity".
In December 2021, 36.2% of the population had been immunized with heterozygous.
So how effective is heterozygous immunity? In fact, "heterozygous immunity" does bring higher antibody levels to different groups than simple vaccination [33-35], but it also cannot prevent the emergence of "reinfection" [32].
In addition, as an article in The Lancet - Infectious Diseases says - infection is accompanied by risks [36].
Therefore, hoping that repeated reinforcement of immunity through "hybrid immunity" is also repeatedly putting the body at risk - unfortunately, the concept of "hybrid immunity" is abused in this way, and many people think that after vaccination, they can be infected naturally at will.
In the face of the risk of repeated infection that may always accompany humans, what people can do is to use these experiences to design and deliver a new generation of vaccines [37], so that there is an increasingly difficult "vaccine door" between infection and health.
3
Mutation and escape of the new coronavirus
What does the next generation of vaccines look like? No one can say because we haven't found the best option yet.
Some people may say that the new crown virus is changing, so our new crown vaccine is also constantly updated like the flu vaccine?
Of course, this is a very desirable and worthwhile approach – after all, we have gained a lot of experience with influenza vaccines, and every year vaccine developers are provided with recommended strains to prepare updated influenza vaccines [38].
However, few people may really realize how quickly the new coronavirus mutates and how quickly it changes during the epidemic.
Trends in novel coronavirus variants[39]
In 2021, the Delta (δ) variant attracted significant attention with T478K, P681R, and L452R mutations in its spike protein (S protein) [40].
However, for the new crown vaccine, whether we can "catch up", "predict", "continue to be effective", no one can say accurately. Of course, it is not without the way that research and development institutions have adopted variant vaccines, even multivalent variants.
When bivalent vaccine studies including Alpha/Beta, Delta/Omicron BA.5, WT/Omicron BA.1, and Omicron BA.4/BA.5 were published, the data showed a better immune response than the new crown vaccine based on the original strain [41-44], which also brought great encouragement to promote the research and application of variant vaccines.
However, with the emergence of new variants of the coronavirus, particularly the Omicron variant, some of the seemingly exciting data seems to be becoming less exciting.
Due to the priority of increasing humoral immunity levels, after the bivalent vaccine against variant strains was launched, some experts believed that the humoral immunity improvement brought by bivalent mRNA vaccines compared with the original strain vaccine was unlikely to be clinically significant [45], and from the perspective of immunogenicity, whether monovalent, bivalent, booster immunization, and heterozygous immunity were very effective against some Omicron variants, but when Omicron XBB arrived, humoral immunity levels decreased dozens of times [46-48].
Image from the bibliography [48]
The impact of the new coronavirus has even challenged the effectiveness of vaccines, and even the suppressive activity of therapeutic or preventive monoclonal antibody products that were once highly hoped for has seriously decreased [49]. According to the U.S. Food and Drug Administration (FDA), the only prophylactic monoclonal antibody authorized for emergency use was withdrawn for emergency use because it was not effective in preventing infection with the new Omicron variant [50,51]. However, humoral immunity levels do not reflect vaccine effectiveness, and in previous studies have found that T cell immunity plays an important role in the protection of the body [52,53], real-world data also show that bivalent vaccines based on variants have better efficacy against new variants than monovalent vaccines based on the original strain [54,55]. The data showed that after the bivalent new crown vaccine was used as the third or fourth dose of vaccination, the protection against hospitalization caused by BA.5/BQ.1/BQ.1.1 was 58.7%, and the overall protection against hospitalization deaths was 61.8%; The monovalent vaccine as the third or fourth dose to prevent BA.5/BQ.1/BQ.1.1 was 25.2% and the overall protection against in-hospital deaths was 24.9%. Remember the earlier effectiveness against "various infections" mentioned earlier? Yes, 95%. At this time, even bivalent variant vaccines have not reached this number. At this time, it seems that a new, broad-spectrum, higher antibody level and better durable new crown vaccine is needed. It happened that at this time, a "nanoparticle vaccine" that was personally praised by the owner of the self-media platform came into being.
Research on ferritin-based nanoparticle vaccines[56]
Researchers have prepared vaccines using the full-length extracellular domain (S-Fer) of the main antigen of the new coronavirus (S protein) or the C-terminal 70 amino acid residue deletion (SΔC-Fer) combined with Helicobacter pylori ferritin to form nanoparticles to prepare a vaccine, which can produce broad-spectrum, high-level antibodies to resist the new coronavirus and have good persistence [57].
However, this vaccine is still in the animal testing stage for the time being, and this vaccine is only a small step towards "providing effective protection against the new coronavirus for at least 1 year".
In the face of various new coronavirus variants, perhaps in addition to updating vaccine components more frequently than influenza vaccines, we still have not found a long-term solution.
As the new crown virus continues to mutate, the immunogenicity and effectiveness of the vaccine may be able to be responded to by vaccine updates, but so far it has not been found to be a good enough "broad-spectrum vaccine", perhaps a better way is to increase the number of new crown vaccines?
4
Antigenic original sin with harmful IgG4
Here's the good news: every vaccination or infection stimulates the immune response again, which increases resistance to the coronavirus. So in the face of the new crown virus, isn't it enough to go over and over and get vaccinated a few more times?
But perhaps, you have also heard the word: "antigenic original sin".
The "Original Antigenic Sin" is also known as the "Hoskins effect".[58] This phenomenon simply means that after the initial immunity, after the same but slightly different pathogens (or vaccine antigens) invade the body again, the body will preferentially consume the immune response generated by the initial immune memory, rather than mobilize a new immune response to deal with the pathogen, eventually resulting in a decline in the immune response, and even unable to produce enough effective protection against similar antigens.
To put it simply: after previous infection or vaccination, when encountering a "slightly altered virus", the antibodies produced by the previous memory B cells can neither kill the virus, but also delay the new B cells to produce new effective antibodies - that is, immune memory is helping[59].
Before the new crown hit, including influenza, dengue fever, bocavirus infection, human papillomavirus infection, human immunodeficiency virus infection, etc. [60-63] have found the phenomenon of "antigenic original sin", unfortunately, the new crown has also appeared in the same situation, and even has been manifested in new crown infection and new crown vaccines.
In the application of the new crown vaccine, although there is not much relevant research information, there is indeed an immune response phenomenon that may be related to "antigenic original sin", and it is not only a new crown vaccine of a technical platform [64,65]
The fourth dose did not significantly improve humoral immunity compared with the third dose [66]
The disadvantages of multi-dose vaccination are not only in the level of antibodies, but also in the level of antibody quality.
Studies have found that receiving a booster dose of the new crown vaccine can improve the breadth of antibody spectrum against the new coronavirus, which also helps the body defend against different new coronavirus strains, including the Omicron variant [67], but as mentioned above, even 3 or even 4 doses of the vaccine cannot induce a sufficiently ideal humoral immune response to the variant.
To make matters worse, a class of antibodies called IgG4 is also of increasing interest.
The primary role of antibodies is immunomodulatory and antipathogen [68], but in a study of people who completed three doses of the vaccine, the median proportion of IgG4-transformed B cells in the entire B cell pool increased from 1.3 percent (IQR 0.9–2.2 percent) after the second dose to 14.4 percent (IQR 6.7–18.1 percent) [69].
Why focus on IgG4, which is becoming more and more important? Because it is associated with a reduced ability of antibodies to mediate antibody-dependent cell phagocytosis and complement deposition, and even in previous studies in Brazil, high levels of IgG4 were associated with more serious consequences after infection with the novel coronavirus [70].
Therefore, there are concerns that the high levels of IgG4 produced after repeated vaccination will increase the serious consequences of reinfection.
Fortunately, no such problems have been found now.
5
Preventing the new crown, where the road is
The new crown virus can be said to be an extreme problem given by nature to the medical community -
Rapid slap in the face: When humans make a vaccine, the virus mutation will make the vaccine less effective against infection;
False weakness: even if it seems that the virulence decreases after mutation, the increase in infectivity does not reduce the burden of disease;
When the vaccine is updated through science and technology, the mutation speed of the virus makes the new vaccine shameful;
Potential harm: the existence of "original sin" and "IgG4" is also a constant reminder that people cannot solve the problem in a single way.
Perhaps this information is very negative, giving people the idea that humans cannot resist the new crown attack, and even think that the new crown vaccination is no longer meaningful.
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However, this is not the case.
While there is a lot of "bad news in theory," there is a lot of "good news about the real situation."
On the one hand, we can still reduce the risk of contracting the new coronavirus through traditional methods (non-pharmacological interventions), including standardizing the wearing of masks [71,72], hand hygiene [73,74], indoor ventilation [75], and nutritional intake [76].
On the other hand, even if there is a decrease in the neutralizing activity of new coronavirus antibodies against variants, the new crown vaccines developed by both traditional and new technology platforms are effective in the real world, especially the protection against severe disease and death [77-80].
At the same time, many of the so-called vaccine "negative news" just mentioned is still stuck in "theory", although the theory has confirmed the possible shortcomings and even risks of some vaccines, but these have not been confirmed by "facts".
Just as many people think that antibodies will only be effective when they reach a "protective level", this is true in theory, but in reality the immune response is not done by antibodies alone.
Therefore, the development direction of future vaccine applications is very clear: improve vaccine antigen categories [81], improve vaccine design ideas, change vaccine immunization strategies[69], and change information management methods (control of vaccine rumors).
Distribution in vivo in mice of monoclonal antibody mice after nasal drops[82]
In addition to vaccines, many R&D institutions are also actively promoting the research and development of broad-spectrum monoclonal antibodies [83-86], and improving the route of administration to make the compliance of related products better, so as to solve the problems of virus escape mutation and immune stress screening through broad-spectrum antibodies.
So what can be done now? Just three points:
Pay attention to protection, vaccination, standardized treatment.
It's easy, but it's hard to do.
May the world be free of epidemics
pill
Disclaimer: This article is created for personal interest, only to let more ordinary people have a clearer understanding of vaccines, the content views do not represent any organization, unit, institution, do not accept any form of sponsorship, all pictures are from research papers or have paid to purchase personal use rights, if the content is wrong, everyone do more self-criticism (not).
Resources
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