Coronavirus disease 2019 vaccines: challenges of using global mass vaccination to achieve herd immunity : Chinese Medical Journal

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Coronavirus disease 2019 vaccines: challenges of using global mass vaccination to achieve herd immunity

Bao, Pengtao1; Gong, Jiuyu2; Mu, Mi1; Que, Yifan3; Hu, Peng3; Luo, Jiang4; Chang, Christopher5,6; Xu, Guogang4

Editor(s): Ni, Jing

Author Information
Chinese Medical Journal ():10.1097/CM9.0000000000002270, February 14, 2023. | DOI: 10.1097/CM9.0000000000002270

To the Editor: To control the coronavirus disease 2019 (COVID-19) pandemic and reduce the complications and deaths resulting from the transmission of the disease, a variety of COVID-19 vaccines, such as mRNA vaccines, adenovirus-vector vaccines, inactivated viral vaccines, and others, have been licensed for emergency use. Most of these vaccines were rolled out in different countries following the successful completion of phase 3 clinical trials. Scale-up of vaccine production and vaccination have provided notable protection to large populations, although some vaccines may cause side effects. Furthermore, as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has mutated and spread further over time, some notable novel variants have emerged but whether these variants are vulnerable to currently available vaccines is yet to be determined.

Despite the availability of vaccines across the world varies and some countries are still struggling to obtain vaccines and effectively store vaccines, a large proportion of people have now been vaccinated. An international consensus has been reached on the use of global mass vaccination to curb the epidemic. Remarkable achievements are demonstrated because the severity and mortality rate have decreased significantly compared with early 2020. Therefore, it is appropriate to evaluate and reassess the current epidemic situation and formulate timely plans to achieve herd immunity.

To date, there have been 337 candidate COVID-19 vaccines that have been reported or registered worldwide [Supplementary Figure 1,]. Of these, 142 are undergoing clinical development, while the rest of them are in preclinical trials. The protein subunit is the most commonly used platform, accounting for 33% of all vaccine candidates. Most current vaccines are on a two-dose schedule to achieve optimal immunity against SARS-CoV-2. Most candidates are administered by intramuscular injections. The mechanisms for how different vaccines act on the immune system are presented in Supplementary Figure 2, Based on the different production mechanisms, vaccines are mainly classified as inactivated vaccines, protein subunit vaccines, vector-based vaccines, mRNA-based vaccines and deoxyribonucleic acid (DNA) based vaccines, virus-like particle vaccines, and live-attenuated vaccines. According to World Health Organization (WHO), the vaccines procured the most are Comirnaty (Pfizer BioNTech, America-Germany), Spikevax (Moderna, America), Vaxzevria (AstraZeneca, Britain), Covishield (SII, India), and CoronaVac (Sinovac, China). The characteristics of the selected vaccines are listed and compared in Supplementary Table 1,

Live-attenuated vaccines might possess a risk of viral infection and transmission. DNA vaccines in nucleic acid vaccines present the risk of oncogene activation, inactivation of tumor suppressor genes, accidental replications, or chromosomal instability due to the potential integration into the host genome. mRNA could bind to endosomal or the cytosol pattern recognition receptors before translation. Endosomal single-stranded or double-stranded ribonucleic acid (RNA) can be recognized by toll-like receptor 3, 7, and 8, while short and long filaments of double-stranded RNAs may be recognized by retinoic acid-inducible gene-I in the cytoplasm, as well as melanoma differentiation-associated protein 5. The subsequent activation of innate immunity can theoretically generate pro-inflammatory cascades, for instance, inflammasome formation and activation of the nuclear transcription factor-kappa B pathway.[1] This might lead to several potential adverse side effects or induce autoinflammatory or autoimmune conditions. Neutralizing antibodies generated from previous adenovirus infections might potentially prevent human cells from incorporating the adenovirus vector, or impact adenovirus vector vaccine safety by initiating an inappropriate immune response.

Most adverse reactions occur during the window period after vaccination. Almost all anaphylactic reactions (injection site redness and swelling, fatigue, and fever) occurred within 15 to 30 min.[2] Therefore, 30 min is recommended as the observation period post-vaccination for those individuals at risk of allergic reactions. The incidence of adverse reactions from adenovirus and mRNA vaccines was higher than that of other vaccines. Severe adverse reactions were rarely seen in adults,[3] and the incidence rates of anaphylaxis and myocarditis were reported to be 2.5 to 4.8 billion and 6 to 27 billion for mRNA vaccines, respectively. Thrombosis with thrombocytopenia syndrome was reported as an adverse reaction for the AstraZeneca vaccine (2 billion), while for the Ad.26.COV2.S vaccine (Johnson & Johnson, USA), thrombosis with thrombocytopenia syndrome (3 million) and Guillain–Barré syndrome (7.8 million) were reported. Transverse myelitis (1 million) was reported for BNT162b2. Capillary leak syndrome and multisystem inflammatory syndrome were possible side reactions for AZD1222 (AstraZeneca, Britain). The major severe adverse reactions are summarized in Supplementary Table 1,

SARS-CoV-2 vaccines have been developed in a relatively short time after the initial outbreak, using knowledge gained from SARS and Middle East respiratory syndrome vaccines. The Spike protein, a large transmembrane protein I that contains a receptor-binding domain (RBD), is a common antigen target in vaccine development. The RBD spike protein fragment, widely used in vaccine development, is considered highly antigenic and plays an important role in humoral and cellular immune responses. This protein also induces neutralizing antibodies that play an essential role in protective immunity by preventing host cell attachment and infection.

Furthermore, when used in conjunction with S protein epitopes, conserved nucleocapsid (N) and membrane (M) proteins could synergically enhance immunogenicity, and T cell and cytokine release. At present, SARS-CoV-2 epitope vaccines based on polypeptide subunits include the adjuvant, cytotoxic T cells, helper T cells, and B-cell epitopes. Non-toxicity, non-sensitization, thermostability, and the capability to induce humoral and cell-mediated immunological reactions are advantages of these vaccines. The key to designing peptide vaccines is the recognition of B-cell and T-cell epitopes that are immunodominant for specific immune responses.

Variants of the SARS-CoV-2 spike protein have been reported worldwide. The spike protein is highly glycosylated; therefore, new variants may have different infectivity and antigenicity. Newly emerging, fast-spreading variants of SARS-CoV-2 can also reduce the overall protective effects of vaccines. Based on the transmissibility, pathogenicity, and immunogenicity, significant variants are divided by the WHO into a “variant of concern (VOC)” and “variant of interest.” There are currently five VOC mutants identified by the WHO: B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), B.1.617.2 (Delta), and B.1.1.529 (Omicron). As there have been many reports on the previous variants, including alpha, beta, and gamma, we focus on the current primary strain with high transmissibility. Former data are summarized in Supplementary Table 2,

With up to 37 amino acid mutations on its S protein, the spike protein of the Omicron mutant exhibits a stronger binding ability to angiotensin-converting enzyme 2, which explains the potential mechanism underpinning its enhanced infectivity. Moreover, Omicron is believed to be associated with a higher risk of reinfection and a significantly enhanced immune escape ability, although the underlying mechanism remains unclear. As reported, the neutralization of the Omicron variant was undetectable in most vaccines, which may result from its ominous antigenic properties. The emergence of the Omicron variant has raised concern over the efficacy of neutralizing antibodies induced by COVID-19 vaccines as many vaccinated individuals have been infected with Omicron. Two BioNTech vaccinations, which provide more than 90% protection against serious Delta variant infection, may be significantly less effective against Omicron. Neutralizing antibodies against omicron were detectable in only about 20% to 24% recipients of BNT162b2,[4] and undetectable in all Coronavac recipients. The geometric mean neutralization antibody titers (GMT) against the Omicron variant in BNT162b2 recipients were significantly lower compared with Beta and Delta variants. Laboratory investigations suggest that Pfizer-BioNTech vaccines appear to offer better protection from the Omicron with a third dose as a booster, the latter of which increase the neutralizing antibody titers by 25-fold compared with the other two doses. Notwithstanding the low efficiency of the current vaccines against the novel variant, vaccines seem to have the potential to reduce the severity and death rate in individuals infected with omicron. The results about effectiveness of a few vaccines on omicron published on scientific journals are summarized in Supplementary Table 3,

Herd immunity refers to the interrupted transmission of the disease in a biological population that occurs when most individuals have developed immunity to pathogens. There are two main ways to achieve herd immunity: natural infection (passive immunity) or vaccination (active immunity). Current studies estimate that the basic reproduction number (R0) of COVID-19 is 2.5 to 5.8 in different studies,[5] which translates to a predicted herd immunity threshold of between 60% and 83%. In clinical trials, the vaccine efficacy has been reported to be between 60% and 95%, depending on the vaccine. These calculations indicate that higher vaccination coverage may be needed to interrupt transmission. Ultimately, with the global population approaching 8 billion, 11 billion doses, depending on the type of vaccine, may be needed to stop transmission.

It seems that it is no longer reasonable to obtain herd immunity from natural infection, as individuals became reinfected even though the positive rate of serum antibody is high after the first infection. Previous infections cannot protect individuals from the epidemic due to the constant mutations of the virus. It was estimated that 250,000 might result from the policy of natural herd immunity. Thus, many countries that used to develop herd immunity by the natural infection have now resorted to the weapon of vaccines. In a previous study, among the residents who received at least one dose of vaccine, there were 822 novel coronavirus cases (4.5% of the vaccinated residents) from 0 to 14 days and 250 cases (1.4%) from 15 to 28 days. The infection rate of residents vaccinated with two doses of vaccine decreased from 1.0% to 0.3%, while the rate in unvaccinated residents also decreased from 4.3% to 0.3%.[6] Moreover, most infected patients are asymptomatic cases, indicating that the vaccine can not only reduce the infection rate among unvaccinated residents, but also reduce the severity of infected cases, which is consistent with the effect of vaccines on different variants. The WHO has declared that it supports achieving herd immunity through vaccination, rather than by allowing the disease to spread through any segment of the population. Given the fact that the GMT after vaccination usually becomes lower with the emergence of novel variants such as Omicron, whether vaccination is a long-term approach to developing herd immunity remains to be seen.

Sufficiency and efficiency are challenges to developing herd immunity, which may lead to dilemmas in vaccination. Due to the emergence of the Delta variant and the lack of vaccines, the government of England has changed the schedule from providing authorized two doses to one that gives priority to the first dose, and postponed the second dose from 3–4 weeks to 12 weeks. It seems that under the condition of limited resources, a single dose will save more lives. Conversely, a single dose may lead to more vaccine failures or introduce mutations resistant to the vaccine, known as vaccine escape. Another dilemma is the priority of the vaccination afforded to different segments of the population. A study found that giving priority to vaccinating older people can reduce the number of deaths and hospitalizations and save the most lives. However, Indonesia focused on working age adults rather than the elderly to reduce community transmission faster, as adults of working age tend to be exposed to the environment. Besides, the intention of vaccination plays an important part in herd immunity, which depends on regions, the efficiency, type, and side effects of vaccines. According to an anonymous cross-sectional survey, people in Australia (96.4%), China (95.3%), and Norway (95.3%) are more likely to receive COVID-19 vaccines, while people in Japan (34.6%), the U.S. (29.4%), and Iran (27.9%) are unwilling to receive vaccinations. Males, elders, and people with lower education levels seem to be more resistant to vaccination. Vaccines with an efficiency of more than 90% and fewer adverse reactions are more popular, and mRNA-based vaccines are mostly unpopular in countries from the Southeast Asia. The efficiency and adverse reactions are issues of greatest concern, which may shed light on the direction to herd immunity.[7]

In conclusion, vaccines are an important tool to curb the pandemic. Post-licensing studies need to be systematically conducted to investigate the core parameters of herd immunity, as well as the subsequent formulation of policies. COVID-19 vaccines have been developed and released within 11 months after the initial outbreak. In the near future, large-population vaccination and prevention measures still need to be implanted, which would ensure equitable global opportunities for vaccination and ensure immunity to emerging strains of the virus.


This study was supported by grants from the Logistic Support Department of Central Military Commission Health Care Project (No. 21BJZ35) and National Natural Science Foundation of Beijing (No. 7212104).

Conflicts of interest



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