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    Home > Active Ingredient News > Infection > Covid-19 Vaccines – A Review of Immunization, Variants, and Boosters NEJM

    Covid-19 Vaccines – A Review of Immunization, Variants, and Boosters NEJM

    • Last Update: 2022-09-21
    • Source: Internet
    • Author: User
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    As of noon yesterday, although there are about 30,000 cases of new coronavirus infection in Chinese mainland, more than 3,500 high school risk areas have been demarcated, and the epidemic prevention situation is very tense


    Covid-19 Vaccines – Immunity, Variants, Boosters Barouch DHDOI: 10.


    The adaptive immune response is the second line of defense against the virus and involves antigen-specific recognition



    For acute viral infections, including sars-CoV-2 viruses, neutralizing antibodies may be critical in preventing infection from occurring, while humoral and cellular immune responses may control post-infection viral replication and avoid progression to severe illness, hospitalization, and death (Figure 1



    Early data from non-human primate studies showed the protective effects



    The vaccines involve four vaccine platforms: inactivated viral vaccines (Sinopharm's Covidlo, Kerrett's Kerrafol and Bharat Biotech's Covaxin), mRNA vaccines (Moderna's Spikevax mRNA-1273 and Pfizer-BioNTech's Comirnaty BNT162b2), adenoviral vector vaccines (Vaxzevria and Covidshield of AstraZeneca).



    In the United States, four vaccines have been fully approved or authorized for emergency use: the mRNA vaccines BNT162b2 and mRNA-1273, the adenoviral vector vaccine Ad26.



    The mRNA vaccine is the most widely administered vaccine in the United States and Europe, but is relatively limited in developing countries due to cost, need for cryopreservation, distribution logistics issues, and commercial considerations, which contribute to high health inequalities


     

    Table 1.


    * Data on the vaccine's protective efficacy against symptomatic Covid-19 in the United States are from randomized, placebo-controlled Phase 3 clinical trials


    † table shows data



    The Food and Drug Administration and centers for Disease Control and Prevention CDC) recently limited the use of Ad26.
    COV2.
    S in the United States due to the occurrence of rare but severe vaccine-induced immune thrombotic thrombocytopenia (VITT), also known as thrombosis with thrombocytopenia syndrome (TTS
    ).

    VITT occurred in 54 people (9 of whom died), so the incidence was 3 to 4 cases per 1 million vaccinated people
    .

    However, in many developing countries, adenovirus vector vaccines remain first-line vaccines, while VITT incidence in South Africa may be lower than in the United States
    .

    There have also been reports of VITT following ChAdOx1 vaccination in Europe, with an incidence of 13 to 39 cases per 1 million vaccinated people
    .

    The United States also reported 3 cases of VITT (1 of whom died)
    following mRNA-1273 vaccination.

    Myocarditis and pericarditis are complications of BNT162b2 and mRNA-1273, with an incidence of 52 to 137 cases per 1 million vaccinated adolescents and young men after a second dose, and at least 10 deaths
    have been reported.

    Within 7 days of receiving the second dose of mRNA vaccine, the incidence of myocarditis was reported to be 566 cases per 1 million people-years
    .

    Although vaccine-induced myocarditis is mostly mild, it can also cause serious complications
    .

    Changes in cardiac MRI results persist in a significant proportion of young men, even after recovery from myocarditis for at least 3 to 8 months
    .

    But the incidence of thrombosis and myocarditis after Covid-19 infection is much higher than the incidence after Covid-19 vaccination
    .


    Vaccine potency persistence

    BNT162b2 and mRNA-1273 vaccines induce excellent short-term neutralizing antibody responses and protective efficacy
    .

    However, the higher initial serum neutralizing antibody titers induced by the mRNA vaccine decrease within 3 to 6 months and further decline within 8 months, with a half-life of about 60 days
    .

    Unlike BNT162b2 and mRNA-1273, Ad26.
    COV2.
    S induces low initial neutralizing antibody titers, but neutralizing antibody responses and clinical effects are quite durable, lasting at least 8 months
    .

    At 6 to 8 months, antibody responses to BNT162b2, mRNA-1273, and Ad26.
    COV2.
    S were similar
    .

    The data from real-world preventive effect studies were largely consistent with the above immunological data, with BNT162b2 and mRNA-1273 having higher initial protection than Ad26.
    COV2.
    S vaccination, but these differences narrowed
    after a few months.

    Thus, BNT162b2 and mRNA-1273 induce higher initial antibody titers but decline after a few months, while Ad26.
    COV2.
    S induces a lower initial antibody response, but is more durable
    .

    The weakening of immunity induced by mRNA vaccines is associated with an increase in breakthrough infections in vaccinated people, first exemplified by a large-scale breakthrough infection
    of the SARS-CoV-2 delta strain in July 2021 in Provincetown, Massachusetts, USA.

    Vaccinators with breakthrough infections produce a particularly strong immune response, the so-called mixed immunity
    .

    These findings suggest that through the combined effects of widespread vaccination and infection, the number of people immune to SARS-CoV-2 will continue to increase
    .

    Genomic and epidemiological data from the outbreak prove that the virus has
    spread between people who have been vaccinated throughout the process.

    mRNA vaccines and adenoviral vector vaccines induce cellular immune responses that are persistent beyond serum antibody titers
    .

    B cells in germination centers have been reported to persist for at least 6 months
    after receiving the BNT162b2 vaccine.

    CD8+ T cell responses are particularly high after Ad26.
    COV2.
    S vaccine and persist for at least 6 to 8 months
    .

    Because the CD8+ T cell response controls viral replication after infection, the SARS-CoV-2 vaccine may continue to produce significant protection against severe disease even after a drop in serum neutralizing antibody titers
    .

    In immunocompromised populations, both antibody and T cell responses after Covid-19 vaccination are reduced, depending on the degree and type
    of immunosuppression.

    For these populations, more doses of the vaccine and prophylactic treatment
    using monoclonal antibodies are recommended.


    SARS-CoV-2 is a highly concerned variant

    In the spring of 2020, the main strain that had previously been endemic worldwide quickly changed from the original strain to a variant of the SARS-CoV-2 genome carrying four mutations, including a D614G point mutation
    located within the spike protein that gave it an adaptive advantage.

    This was followed by multiple waves of new variants that replaced the previous SARS-CoV-2 strain, which typically exhibited higher infectivity and stronger antibody escape (Figure 2
    ).

    In late 2020, the alpha (B.
    1.
    1.
    7), beta (B.
    1.
    351) and gamma (P.
    1) variants appeared
    in the UK, South Africa, and Brazil, respectively.

    These variants were then replaced globally by delta (B.
    1.
    617.
    2) variants, which emerged
    in India in the summer of 2021.

    In late 2021, the highly contagious omicron (B.
    1.
    1.
    529) variant emerged in Africa and quickly became the most popular strain
    in the world.

    Unlike the delta strain with 4 mutations, the omicron strain has more than 50 mutations, including more than 30 mutations in the spike protein, which gives it a strong ability to escape the neutralizing antibody responses induced by vaccine induction and previous non-omicron strain infection induction
    .

    The omicron strains were rapidly divided into subvariants BA.
    1, BA.
    1.
    1, BA.
    2, BA.
    2.
    12.
    1, BA.
    4, and BA.
    5 (Figure 2
    ).

    The neutralizing antibody titer against BA.
    5 (the current major prevalence strain in the United States) decreased to about 1/3
    of the neutralizing antibody titer against BA.
    1 and BA.
    2.


    Figure 2.
    SARS-CoV-2 variant over time

    Figure A shows the overall and weekly mean number of cases, as well as the FREQUENCy of SARS-CoV-2 variants over time, and Figure B shows the frequencies
    by region.

    These data are based on the Pango lineage
    of sequences collected and shared through the global SARS-CoV-2 sequence collection and published through the GISID database from March 1, 2020 to July 8, 2022.


    Multiple studies have shown that the cross-reactivity between the neutralizing antibodies and the omicron variant induced by various vaccine initial exemption regimens is low, but injecting a booster needle can significantly increase the neutralizing
    antibodies of the omicron variant.

    However, studies have demonstrated that increased neutralizing antibody titers and clinically preventative effects weaken
    within 4 months after receiving the third dose of mRNA vaccine.

    Protection against SARS-CoV-2 omicron infection is reported to diminish after only 4 weeks after receiving the fourth dose of mRNA vaccine, but protection against severe disease can last longer
    .

    Vaccine- and infection-induced mixed immunity can be more potent and long-lasting than either
    .

    The cross-reactivity between the vaccine-induced neutralizing antibody and the omicron variant is limited, while the vaccine-induced T cell response is highly cross-reactivity (>80%)
    between the omicron variant and the previous variant.

    These data suggest that cellular immunity against the SARS-CoV-2 variant is basically intact
    .

    During the surge in the South African omicron strain, two doses of the Ad26.
    COV2.
    S and two doses of BNT162b2 vaccine were 72% and 70% against hospitalization and 82% and 70% against access to the ICU, respectively (Table 1
    ).

    The strong protective power achieved in the absence of substantially no high titer neutralizing antibodies suggests that for severe disease caused by variants that can largely escape neutralizing antibodies, other immune measures (including CD8+ T cell responses and possibly other functional antibody responses) play an important preventive role
    .

    In the United States, cdC data show that the BNT162b2, mRNA-1273, and Ad26.
    COV2.
    S vaccines all provide significant protection against the surge in delta strains in the fall of 2021 and the surge in the winter of 2021-2022 and spring of 2022 (Figure 3
    ).

    In terms of breakthrough infection rate per 100,000 vaccinated people, Ad26.
    COV2.
    S was higher than the mRNA vaccine during the delta strain surge, but Ad26.
    COV2.
    S was lower than the mRNA vaccine during the omicron strain surge, which may reflect the more durable
    immunity induced by Ad26.
    COV2.
    S.

    These data are consistent with the results of real-world studies of preventive effects, which suggest that the mRNA vaccine was initially more effective than the Ad26.
    COV2.
    S vaccine, but the differences between the two diminished or disappeared
    after a few months.

    Figure 3.
    Covid-19 vaccine's protective efficacy in the U.
    S.
    Covid-19 breakthrough infection rate (number of cases per 100,000 vaccinated people) was the infection rate for people vaccinated against BNT162b2, mRNA-1273, or Ad26.
    COV2.
    S vaccine in the United States from April 4, 2021 to May 21, 2022
    .

    The data comes from the US CDC
    .
    Immune indicators related to protection

    Early preclinical studies in non-human primates found that neutralizing antibodies and other functional antibodies were indicators
    of vaccine protection against SARS-CoV-2.

    Adoptive transfer studies using purified IgG confirmed that antibodies alone are sufficient to stop infection
    in non-human primates and hamsters, provided that sufficiently large doses of antibodies are given.

    Studies of CD8 depletion in non-human primates have also shown that CD8+ T cells help play a protective role
    when antibody titers are not enough to produce protection.

    In addition, in non-human primates, vaccine failure in the omicron variant attack test was associated
    with low levels of omicron neutralizing antibodies and CD8+ T cells.

    These data suggest that antibodies alone can stop infection if the antibody titer against the infected strain is high enough, but the combined effects of humoral immunity and cellular immunity are critical
    for virological control after breakthrough infection occurs.

    Analysis of relevant immune markers in the mRNA-1273 and Ad26.
    COV2.
    S trials confirmed that antibody titers were associated
    with protection against symptomatic Covid-19 infection.

    However, these studies were conducted prior to the emergence of the omicron variant, and T cell responses were not included in the
    relevant index analysis.

    For highly infectious variants that can largely escape neutralize antibody responses (e.
    g.
    , omicron variants), protectiveness-related indicators may be more skewed toward cellular immunity
    .

    In addition, in patients with hematological tumors with Covid-19, CD8+ T cells have been shown to be associated
    with survival.

    As mentioned above, during the surge of the omicron strain in South Africa, both BNT162b2 and Ad26.
    COV2.
    S produced strong protection against severe diseases without high-titer neutralizing antibodies against the omicron strain
    .

    In addition, during the surge in beta and delta strains in South Africa, Ad26.
    COV2.
    S developed protection against hospitalization and death without high titer neutralizing antibodies against these variants
    .

    Taken together, these data suggest that neutralizing antibodies are primarily responsible for preventing SARS-CoV-2 infection from occurring, while antibodies and CD8+ T cell responses are critical to preventing severe disease (Figure 1
    ).

    Existing vaccines are less protective against infection and transmission of the omicron variant, even at peak immunity after injection of booster needles
    .

    In addition, the titer of neutralizing antibodies required to prevent infection of highly contagious omicron strains may be much higher than the titers
    required to prevent previous variants.

    Unlike neutralizing antibodies, vaccine-induced CD8+ T cell responses are highly cross-reactive to omicron and may provide great protection
    against severe disease.

    Future studies should focus on the role of mucosal fluids and cellular immunity at the site of vaccination, which may be critical
    in preventing SARS-CoV-2 infection.

    The Covid-19 vaccine strengthens the needle development framework

    We expect the Covid-19 vaccine to prevent infection and prevent its further spread, based on preliminary data from 2020 (before the emergence of the virus variant), which shows high neutralizing antibody titers and strong
    vaccine protection when the mRNA vaccine is at peak after vaccination.

    However, given the significant drop in serum neutralizing antibody titers and the emergence of infectious and antibody-evasive enhancement variants, we should now recalibrate covid-19 vaccine targets
    .

    Existing vaccines may not be able to produce high levels of long-lasting protection against infection or transmission of the omicron variant, even after multiple booster injections and the introduction of an updated version of the omicron-specific vaccine
    .

    The most important goal of Covid-19 vaccination should be to generate long-term protection against severe illness, hospitalizations and deaths from existing and future variants
    .

    Therefore, recommendations on booster needles should consider not only the peak titer of neutralizing antibodies, but also the long-lasting preventive effect
    on severe Covid-19.

    Achieving these protective forces may require a combination of humoral and cellular immunity, with a focus on long-term rather than short-term immune responses
    .

    So far, however, the main focus in the field has been on short-term neutralizing antibody responses
    .

    The potential role of the omicron strain to strengthen the needle is currently being explored, but a study conducted in non-human primates showed that the omicron-specific mRNA vaccine was not superior to the original mRNA-1273 vaccine
    in terms of protection against the omicron variant in the attack test.

    Early clinical studies have shown that if a divalent mRNA vaccine containing both the original strain and the omicron BA.
    1 variant spike immunogen is used as a booster needle, it induces the neutralizing antibody peak titer of the omicron variant strain to be less than twice the
    antibody titer induced by the original mRNA vaccine booster needle.

    Therefore, the clinical benefit of the updated booster needle compared to the existing vaccine is unclear
    .


    Figure 4.
    Adapted from Callaway E [1]

    Heterologous initial immunity-booster (mixed vaccination) regimens (including a combination of mRNA and Ad26 vaccines) are also being studied to assess whether this strategy can improve humoral and cellular immunity intensity and durability compared with either
    type of vaccine alone.

    In addition, early research is underway to develop vaccines for the subgenus sarbecovirus and the betacoronavirus
    .

    Injecting a booster needle every 4 to 6 months to maintain a higher serum neutralizing antibody titer may not be a practical or ideal long-term strategy
    .

    Using the mRNA vaccine as a booster is also not without risks
    .

    In addition, the recommendation to inject boosters frequently may exacerbate "booster fatigue" in the general population, as only 47 percent of people in the United States who are eligible for booster injections have so far been injected with booster needles
    .

    Expert views are still divided on the benefits of frequent injections of booster injections, with the public seeing the confusing and exaggerated information released by public health agencies and the hesitation to vaccinate remains a major challenge
    .

    The recommendation to inject boosters frequently could distract us from key goals (vaccinate large numbers of unvaccinated people in the United States and around the world) and could further exacerbate global health inequalities
    .

    Therefore, vaccine booster programs should be based on reliable scientific data (i.
    e.
    , significant and sustained increase in protection against severe diseases) rather than on short-term increases in neutralizing antibody titers
    .

    Increased community engagement and research may also help reduce misinformation
    about vaccines.

    It is best to be given covid-19 booster injections at a frequency no higher than once a year, and hopefully lower, and a variety of booster injection regimens
    should be made available to the public.

    Vaccine platforms that use more durable protection are ideal
    .


    conclusion

    The Covid-19 outbreak appears to be moving from a hyperacute phase to a endemic phase
    .

    The existing Covid-19 vaccine is less effective in preventing infection of the omicron strain than it is in previous variants, but the protection against severe disease is largely maintained
    .

    The main goal of the Covid-19 vaccine should be to generate long-term protection against severe illness, hospitalization and death
    .

    Therefore, studies of Covid-19 vaccines and boosters assess not only short-term neutralizing antibody titers, but also antibody responses, memory B cell responses, and cross-reactive T cell response persistence
    .


    References

    1.
    Callaway E.
    New Omicron-specific vaccines offer similar protection to existing boosters.
    Nature 2022; 609:232-233.




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