Microbiological Perspectives in COVID-19 Pandemics: History
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Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Ioannis Alexandros Charitos
,
Andrea Ballini
,
Roberto Lovero
,
Francesca Castellaneta
,
Marica Colella
,
Salvatore Scacco
,
Stefania Cantore
,
Roberto Arrigoni
,
Filiberto Mastrangelo
,
Mario Dioguardi

The COVID-19 pandemic caused by SARS-CoV-2 remains a significant issue for global health, the economy, and society. When SARS-CoV-2 began to spread, the most recent serious infectious disease of this century around the world, with its high morbidity and mortality rates, it is understandable why such infections have generally been spread in the past, mainly from international travel movements. Microbiology is a branch of medicine and biology that studies the structure and functions of microorganisms (i.e., all those single-celled, multicellular or acellular living organisms not visible to the naked eye such as bacteria, Archaea, some types of fungi, algae, protozoa, viruses and prions).

  • SARS-CoV-2
  • human vaccines
  • COVID-19
  • pandemic
  • Pubblic health
  • Epidemiology
  • Infections
  • Viruses
  • Health care management

1. Diagnostic Tests and Screening

The rapid recognition of a microorganism such as this virus comes from collaborative research that uses high-tech laboratories with access to manifold techniques, from cell culture to electron microscopy and molecular microbiology. This demonstrates how a very well-organized effort may be able to respond to the threat of new infectious diseases that may arise in the 21st century [1][2][3]. Experience with SARS-CoV-2 also points out that a lack of cooperation can seriously hamper scientific progress and have serious consequences. It is not always known whether a microorganism such as SARS-CoV-2 can be permanently eliminated. It is up to researchers to rapidly detect and monitor pathogens for the health of humanity. Misdiagnosis of the etiology of an infectious disease could alter the trajectory of patient care, resulting in the unnecessary execution of diagnostic tests or prescriptions of antiviral, antibiotic, antifungal, and antiparasitic medications [3][4]. The abuse of antibiotics often reflects the difficulty of clinically discriminating bacteria from viral infections or other similar diseases. Thus, medical history, physical examination, and other ancillary examinations often do not provide definitive discrimination. To address this problem, effective tests must be put in place for the rapid recognition of bacterial or viral diseases [2]. In this field, microbiological research needs to be expanded for adjuvant therapy with bacterial strains that are beneficial to the human microbiota, and which use probiotics and stem cells during viral infection [5][6][7][8][9]. Moreover, because the aspiration of oral bacteria induces the expression of angiotensin-converting enzyme 2, a receptor for SARS-CoV-2, and production of inflammatory cytokines in the lower respiratory tract, poor oral hygiene can lead to COVID-19 aggravation [10][11][12][13][14].
The main resources for microbiology laboratories are antigen or antibody tests as well as pooling procedures or specimen collections. One of them is called immunoXpert ™, an ELISA-based test that accurately distinguishes between bacterial and viral infections and that measures the circulating levels of three host proteins that exhibit distinctive expression and complementary dynamics in host responses against bacterial and viral infections. These are as follows: (a) ligand-induced apoptosis related to tumor necrosis factor (TRAIL); (b) interferon-gamma inducible protein-10 (IP-10); and (c) C-reactive protein (PCR) [15]. The availability of diagnostic methods, in addition to allowing for the rapid diagnosis of SARS-CoV-2 infection, will allow us to better understand the period over which the viral load spreads (and the ability to transmit the infection) during recovery as well as to detect the presence of the virus in various biological fluids and its presence and excretion during the incubation period [16].
The throat swab searches for the progressive infection (as it searches for whether the virus is present in the airways at the time of examination), while the serological test searches for antibodies that the body has produced against the virus (it evaluates the immunological response produced). Serologic tests may not be as reliable in very recent infections compared to swabs, but they are a tool that allows one to establish whether the body has developed the related antibodies against COVID 19 (it measures the immune system’s response to infection) [17]. There are two types of serological test. The first is a rapid qualitative test (results within 15 min), which is measured through a drop of blood with a lancing device and evaluates whether the person has met the virus by searching for antibodies. The second is a quantitative test, which is exacted through venous sampling and detects the quantity of antibodies. Therefore, both tests detect the immunoglobulins IgM, IgA, and IgG [18]. In a case of acute infection, the presence of IgM is indicated (it is produced first). If the test detects IgG, it means that the infection occurred a while ago (the IgM decreases with the passage of time while the IgG that remains in the blood for life as an immunological memory begins to increase). The first immunoassay was carried out by the Wuhan Institute of Virology in 2020, and others have subsequently been described such as those using rapid detection with the GICA technique (colloidal gold immunochromatographic assay) [19].
Diagnostic tests are performed when a person has signs or symptoms of infection or when they are asymptomatic but have a recent history of known or suspected exposure. However, some diagnostic tests are licensed for use only in symptomatic individuals. In addition, a COVID-19 screening test searches for individual infections in a group (it involves asymptomatic individuals with no known or suspected exposure) to make individual decisions based on the test results [17].
Screening tests are different from diagnostic tests from a health benefit point of view. There are various social communities (such as schools, workplaces, health professionals, etc.) that establish programs for authorized screening tests of asymptomatic individuals with no known or suspected exposure; various testing options are used in these communities. A licensed test is used to perform a screening that is highly sensitive and has fast response times. If the screening test does not have these characteristics, the use of a less sensitive authorized point-of-care test (such as antigen detection) should be considered [18][19].
It is important to note that tests, even in a series, are of limited value if appropriate measures such as quarantine for those who are positive, social distancing, and mask use—even for those who are negative—are not also implemented. Negative outcomes should also be considered “supposedly negative” by health professionals and should be studied in the context of clinical and epidemiological information as well as patient history. If there is doubt with a negative antigen test, the result of a different test may be as different as the highly sensitive authorized molecular one.
Regardless of the test selected, it is important to monitor updates from national or international health control organizations such as the National Institutes of Health and Centers of Disease Control and Prevention (CDC), the FDA, and the WHO as well as the test developer for new information regarding the performance of the selected test with emerging virus mutations in the community [19][20]. It is important to note that tests, even in a series, are of limited value if not combined with appropriate mitigations for individuals who test positive such as quarantine, good contact traceability, effective behavioral protocols (such as wearing a mask), handwashing, and social distancing, even for subjects who test negative [20][21].

2. Vaccination Campaign

Both drug therapy and individual protective devices are needed to fight an infectious viral or bacterial pandemic. As in the current case of the COVID-19 pandemic, therapy cannot always prevent contagion. Current therapy for COVID-19 is based on dexamethasone, tocilizumab, remdesivir, and baricitinib in combination with remdesivir, anticoagulation drugs, three monoclonal antibody treatments (authorized by the FDA), and corticosteroids (such as dexamethasone) [22]. Since the first vaccine conceptualization and development, humans have eradicated some serious infections such as smallpox and polio, but have also sought to prevent other forms of infection. It must be mentioned that in the first quarter of 2020, there was a drop in vaccination coverage from other infections from 10% to 50% compared to 2019 due to the implementation of strict social and physical distancing policies in many countries around the world. Indeed, during this same period, polio, measles, and other vaccination campaigns were suspended due to concern over COVID-19 transmission in campaign settings [23]. The content of the vaccine introduces its component into the body and is recognized by the immune system, subsequently, when the body encounters the foreign entity again, the bacterium is activated and develops antibodies and memory cells. This is thanks to immunological memory, which can last for several years (thus protecting us from possible reinfections) [24]. There are various types of vaccine that differ in their compositions, namely: (a) live attenuated, which contains viruses or bacteria that are still alive but rendered harmless and therefore no longer capable of causing disease (such as that used for measles); (b) inactivated, in which viruses or bacteria have been killed through heat or with a chemical treatment (such as polio or IPV); (c) subunit vaccines (do not contain any whole bacteria or viruses) such as the recombinant protein (hepatitis B, HPV, and meningococcal B or MenB vaccines), toxoid (diphtheria, tetanus, pertussis vaccines), conjugate (H. influenzae b or Hib, meningococcal C or MenC, pneumococcal conjugate or PCV vaccines), virus like particles (hepatitis B and human papilloma virus or HPV vaccines) and the outer membrane vesicles (MenB or meningococcal B vaccine); (d) nucleic acid vaccines are the messenger RNA (such as mRNA COVID-19) and DNA vaccines (currently not licensed); and (e) viral vectored (have a harmless viruses to release the genetic code) and can be replicating (such as the Ebola vaccine) or non-replicating (such as the COVID-19 vaccine) [25][26]. Until a high level of stability is achieved and the quality of microbiology laboratory methods for SARS-Cov-2 detection is maintained, the results of laboratory methods should be evaluated with caution in various clinical situations. Physicians are strongly advised to consult the updated recommendations of the WHO and global organizations on the availability and use of new diagnostic methods. It is possible that the SARS-CoV-2 virus persists in an unrecognized animal reservoir from which it can once again jump into the human population. There are currently effective vaccines in animals to prevent coronavirus infections [16][27]. The effectiveness of the vaccine was first demonstrated in appropriate animal models, and it takes time to demonstrate its safe use in humans. Several factors such as age, comorbidities, and variants of the virus can have a negative impact on the effectiveness of vaccines [26][28]. In fact, the WHO reports that it is not yet known how long the immunity from the various vaccines currently in circulation will last. For this reason, all public health measures including physical distancing, face masks, and hand washing should be used. It has been noted that protection gradually increases and, that after 14 days, significant levels of protection occur. For a single-dose vaccine, protection is generally believed to occur within two weeks of vaccination compared to two-dose vaccines [29]. The vaccine types currently in use for SARS-CoV-2 are as follows: (a) mRNA (messenger RNA, which contains material from the virus that causes infections); (b) protein subunit, which includes harmless pieces (proteins) of the virus that causes COVID-19 instead of the entire germ; and (c) the viral vector, which contains a modified version of a different virus with material from the virus that causes COVID-19 (Figure 1) [30]. The function of the mRNA vaccine is to transmit a message of life contained in the DNA so that the cell can subsequently use it to produce proteins that are needed for life. RNA is a fragile molecule because it is usually present in the cell during its action, as opposed to DNA. For this reason, this type of vaccine can be stored at temperatures as low as −90 °C [30]. The mRNA is encased inside spheres made of liposomes. Once injected into the human body, these lipid spheres release the specific mRNA. In fact, it contains the information to produce the spike structural protein of the virus; this is the key to cells multiplying and causing infection. Once the mRNA vaccine enters the cells, ribosomes translate its information into proteins; in other words, they produce many copies of the SARS-CoV-2 spike protein. Once produced, it leaves the cell and is recognized as a foreign entity by the immune system, which activates a reaction against it but without causing disease; this is because it represents only a small part of the viruses’ structure, but it also triggers the memory cells (Figure 1) [31].
Figure 1. To date, five safe and effective vaccines against COVID-19 have been following positive scientific recommendations. Others are in the process of experimentation [32][33].
An unprecedented worldwide effort to develop safe and effective COVID-19 vaccines began in January 2020 and rolling out in December 2020. The goal of facilitating fair and equitable access to COVID-19 vaccines gave birth to the institution of the COVAX Global Vaccine Facility co-led by the WHO, Gavi, and the Coalition for Epidemic Preparedness Innovations, in collaboration with UNICEF and others. In addition, the Strategic Advisory Group of Experts on Immunization (SAGE) approved by the WHO gave recommendations for any COVID-19 vaccine [34].
The involvement of the pharmaceutical–diagnostic industry is clearly desirable and necessary, but the problems that may arise from “exclusive copyright” must not create obstacles in the pursuit of scientific development [31]. According to the European Center for Disease Prevention and Control (ECDC), the assessment of the risk represented by the SARS-CoV-2 pandemic and the predominance of the Delta variant can be evaluated according to the division of the total general population into two groups: the vaccinated and the unvaccinated, which themselves contain two other groups—the vulnerable vaccinated and the vulnerable unvaccinated. This stratification occurs through some important considerations. Vaccinated people are less likely to become infected, and the impact of the disease is less pronounced than it is in unvaccinated people. Moreover, the population that is vulnerable is more likely to suffer from severe infection. In countries with COVID-19 vaccination coverage equal to or below the current EU average level in the total population, and those planning to ease very high viral circulation non-pharmaceutical interventions (NPIs), fully vaccinated vulnerable populations are also at risk of infection, which could lead to a severe outcome [23][35][36][37][38][39]. In contrast, countries with COVID-19 vaccination coverage above the current EU average level, particularly those with the highest current coverage in the total population, have a lower risk in this respect, unless there is a rapid decline in vaccine efficacy due to decreased immunity. In EU countries with COVID-19 vaccination coverage equal to or lower than the current average (60–80%) level in the total population, and those that plan the easing of non-pharmaceutical interventions, viral infections (high viral circulation) will be very high, meaning that vulnerable vaccinated populations are also at risk of infection, which could lead to a severe outcome. Conversely, countries with a vaccination coverage above the current average (60–80%) or high level (80%>) in the total population have a lower risk in this respect, unless there is a rapid decline in vaccine efficacy due to decreased immunity (Figure 2) [39].
Figure 2. The vaccination trend rate in the continents until 17 August, 2022. The WHO target is 70% of the vaccinated population by mid-2022. According to the WHO, 67.4% of the world’s population has received at least one dose of the COVID-19 vaccine. * Doses administered per 100 inhabitants, ** Share of the world total of doses administered [40][41][42][43].
Finally, an experimental model found that the highest risk of establishment of resistant strains occurs when a large fraction of the population has already been vaccinated but transmission is not controlled [36][40].
Currently, the goal of the COVID-19 vaccination campaign around the world continues to be essential because it reduces hospitalizations, complications, and deaths while protecting health systems, so vaccination has continued with three booster doses, even extending from the age of 5 years old [41]. According to the WHO, nearly one billion people in low-income countries are not vaccinated. Only 57 countries have vaccinated 70% of their population, almost all of them high-income countries. In fact, the latest mean of doses administered each day (in the seven last days) in low- and middle-income countries is 425,961. At this rate, the target to cover 70% of the vaccinable population would be reached by January 2030 [42][43]. The inequalities related to COVID-19 vaccination access in the population must be effectively addressed. In general, it is crucial to discover the factors that determine low vaccine prevalence (including issues related to vaccine acceptance and access), so that targeted, effective interventions can be carried out to resolve the issue of correct vaccination diffusion in the population. As for future vaccination strategies, they may also differ depending on the availability of updated vaccines and their characteristics. In fact, various nations can use not only one type of vaccine, but different types for different vaccination strategies depending on the characteristics of the development of the vaccines updated, compared to those used before and considering the emergence of new variants [44].
Like all other vaccines, COVID-19 vaccines can have mild and short-term side effects. These can include fever, fatigue, headache, body aches, chills, diarrhea, and pain at the site of inoculation. However, rather serious (such as allergic reactions) or possibly long-lasting side effects are possible, but are exceedingly rare [45]. Based on available evidence, the WHO recommends that people with a history of severe allergic reactions to any ingredient in the COVID-19 vaccines should generally not undergo vaccination (Figure 3).
Figure 3. The possible adverse reactions or side effects of the vaccines approved and used to date [45].
According to the CDCs, vaccination for COVID-19 is recommended for pregnant women or those trying to get pregnant now or who may become pregnant in the future and while breastfeeding. Pregnant women can also be given the booster dose [38][39].
Furthermore, the evidence on the safety and efficacy of vaccination during pregnancy is increasing. The WHO, on 2 June 2021, recommended vaccination in pregnant women when the benefits of vaccination for the pregnant woman under potential risks (e.g., women who are at high risk of exposure to COVID-19 during pregnancy or with comorbidities that place them in a high-risk group for severe COVID-19). Furthermore, the WHO recommends vaccination in lactating women as in other adults. However, scientific authorities such as the CDC, the WHO, and regulatory authorities monitor the use of vaccines for COVID-19 to identify any problems regarding their safety that could arise to ensure their safe use throughout the global population [39].
Finally, it must be mentioned that the adaptive natural immune response is very important for defense, and thus for patient outcome after SARS-CoV-2 infection and supports the efficacy of the vaccine. The T-cell responses develop early and are related to protection. The T-cell memory includes extensive recognition of viral proteins, estimated at approximately 30 epitopes within everyone (in fact, current vaccines have focused on the spike protein, which contains the ligand epitope for the ACE2 receptor). However, this natural immune memory could limit individual viral mutations and is likely to support protection against severe disease from COVID 19 viral variants (such as Omicron) [46][47]. Hence, the whole COVID-19 (not just a part) provides a wider variety of peptides than antigenic surfaces that T cells can recognize. Current COVID-19 vaccines facilitate potent responses of adaptive immune, and thus the T cells. These defense cells likely contribute to substantial protection against hospitalization or even avoidance of fatality, and novel or heterologous regimens offer the potential to improve further cellular responses. Hence, the immunity that T lymphocytes offer plays a crucial role in the control of the viral disease through the elimination of infected cells, and its importance may have so far been relatively underestimated. On the other hand, the prevention of infection by the host in general or by individual cells will be the responsibility of B-lymphocytes. Therefore, although natural adaptive immunity is better “trained”, that is, more prepared in its surveillance through T-lymphocytes, to give a more robust and effective response, than that induced by vaccines with only the “S” (spike) protein [16][47].
In a retrospective observational study involving 124,500 persons, they were divided into two groups and compared to each other. The first was with SARS-CoV-2 naïve individuals who received a two-dose regimen of the BioNTech/Pfizer mRNA BNT162b2 vaccine, and the second was previously infected individuals who were never vaccinated, acquired immunity of the infected, but unvaccinated people, confers stronger protection against infection with the Delta variant of SARS-CoV-2 than the two-dose vaccine-induced immunity of BioNTech/Pfizer mRNA BNT162b2 [48]. Additionally in another observational cohort study, they evaluated the antibody and cellular immune responses following COVID-19 vaccinations in members of staff and residents at 74 long-term care facilities (LTCFs) across the UK. It was found that the suboptimal post-vaccine immune responses in LTCF-naïve residents needed to improve immune protection through a second dose of vaccine [49].

This entry is adapted from the peer-reviewed paper 10.3390/ijerph191710712

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