Relevance of developmental origins of health and disease (DOHAD)

The first 1000 days of life including gestation are critical periods for human development. Infants in their first 2 years of life are vulnerable since they undergo rapid growth and development. While the neurological and linear growth development is compromised chronically following nutritional deficiency, environmental factors contributing to compromised immunity cannot be ignored. ^{Reference Martorell5} Rapid development during the first 2 years of life, if dysregulated, can manifest later in adulthood. Age-dependent immunity has been observed due to the lack of adaptive immunity and differentiated innate immunity in children. ^{Reference Maggini, Pierre and Calder6} The phenomenon is not pathological as environmental priming of the immunological system may be attainable after 2 years of age. Immunological responses are the combination of gene–environment interactions. The developmental origins of the health and disease (DOHaD) hypothesis have gained prominence since the last few decades that correlates adult disease to childhood, or in utero exposures. ^{Reference MacGillivray and Kollmann7} The immunological responses are the prototype example of the DOHaD concept due to the complex gene–environmental foreplay, especially through epigenetic modifications. The differential environmental exposures owing to socio-geographic contributors result in epigenetic reprogramming and lead to variable trained innate immunity. Cell ontogeny in the context of immunology epigenetics may contribute to the global variation of COVID-19 mortality and outcomes. ^{Reference MacGillivray and Kollmann7} As global efforts are being made to optimize vaccines, it is fundamental to carry out regional assessments of population-based immunological responses.

Methodology

This study reviewed databases including MEDLINE, Scopus, CINAHL Plus, and WHO Global Database. No restrictions were applied on the data search and the search encompassed articles from inception until September 1, 2020. We used the following search terms with Boolean operators including “immunology”, “age”, “innate”, “adaptive”, “vaccine”, and “COVID-19”. We did not exclude any type of study and the reference list of included articles was also searched (umbrella review). Journals including NEJM, the Lancet, JAMA, and the BMJ were manually searched for relevant articles. Two investigators (AS, ZS) searched for data from the included studies with a third investigator (NTI) solving any disagreements for the narrative review.

Structure, genome, and viral life cycle

The coronavirus consists of a positive-sense, single-stranded RNA (+ssRNA) molecule. The size of the coronavirus genome ranges between 26,000 and 32,000 bases and it is among the largest known RNA viruses. ^{Reference Gorbalenya, Enjuanes, Ziebuhr and Snijder8} The genome size of SARS-CoV-2 varies from 28.9 kb to 29.9 kb and incorporates up to 9–14 open reading frames (ORFs). ^{Reference Gorbalenya, Enjuanes, Ziebuhr and Snijder8,Reference Khailany, Safdar and Ozaslan9} The gene segments translate ORF1a and ORF1b, constituting two-thirds of the genome length and is present at the 5′end, to produce two overlapping polyproteins, pp1a and pp1ab. ^{Reference Masters, Kuo, Ye, Hurst, Koetzner and Hsue10} Four major structural proteins and different accessory proteins encoded by other ORFs are located at the 3′ end. Structural proteins contribute to the viral assembly and host tropism including spike (S) protein (recognizes host cell receptors), envelope (E) protein (assembles and releases virion), membrane (M) glycoprotein (shapes the virion), and nucleocapsid (N) protein packs the RNA genome. ^{Reference Siu, Teoh and Lo11} The life cycle of SARS-CoV-2 is summarized in Fig. 1.

Fig. 1.

The life cycle of SARS-CoV-2. The virion binds to its receptor angiotensin-converting enzyme 2 (ACE2) on the cell surface through its spike protein (S) with the help of either cellular transmembrane serine protease 2 (TMPRSS2) or cathepsin L as mediator. Receptor-bound virion particles enter into the cell through endocytosis and ultimately viral envelop fuses with endocytic vesicle membrane releasing viral nucleocapsid inside the cytoplasm. The helical viral nucleocapsid is uncoated and the viral genomic ORFs 1a and 1b encoding the viral replicase complex translates into two polyproteins, pp1a and pp1ab. Proteolysis of pp1a and pp1ab leads to 16 non-structural proteins (NSPs). The NSPs contribute to the formation of a replication–transcription complex (RTC) in double-membrane vesicles (DMV). RTC in DMV mediates positive-sense, negative-sense, subgenomic, and genomic RNA synthesis to promote replication and cellular evasion. The viral genome encodes structural proteins S, E, and M, and other accessory proteins translated by ribosomes attached to the endoplasmic reticulum. Structural protein N is assembled with newly synthesized viral genomic RNA in small vesicles and fuses with virion precursor and is transported to the endoplasmic-reticulum–Golgi intermediate compartment (ERGIC). Following virion encapsidation, budding and maturation occur after which the newly assembled virions are exocytosed to out of host cell. Adapted from. ^{Reference Jiang, Hillyer and Du55}

Age-dependent immunological responses

The immune system is derived from the hematopoietic stem cells (HSCs) that differentiate into the innate and adaptive immune systems. ^{Reference Montecino-Rodriguez, Berent-Maoz and Dorshkind12} The immune system undergoes maturation throughout the life due to different environmental stimuli. The innate immune system, formed by the neutrophils, macrophages, and dendritic cells, are the gatekeepers of immunological responses. The adaptive immune system, constituted by the T cells and B cells, is also markedly impaired in the first 2 years of life. ^{Reference Maggini, Pierre and Calder6}

Inflammatory pathogenesis in adult populations

As part of its natural replicative cycle, SARS-CoV-2 is a cytopathic virus that induces the death of cells and tissues. ^{Reference Park, Kwon and Choi38} Epithelial and endothelial cells undergo apoptosis and vascular leakage triggers the rise of cytokines and chemokines to induce an inflammatory state. ^{Reference Yang39} Importantly, pyroptosis is an inflammatory programmed cell death of infected cells via activation of NLP3 inflammasome and release of interleukin-18 (IL-18) and interleukin-1 beta (IL-1β) for active recruitment of immune cells at the site. ^{Reference Yang39} In some people, a dysfunctional immune response is followed by massive immune cell proliferation and overproduction of cytokines resulting in cytokine storm syndrome. ^{Reference Tay, Poh, Rénia, MacAry and Ng40} The induction of an aberrant inflammatory response is associated with acute respiratory distress syndrome (ARDS) and multi-organ involvement. ^{Reference Zhang, Zhou and Qiu25} The clinical manifestations of severe COVID-19 are associated with the release of proinflammatory cytokines known as cytokine storm syndrome. The induction of an aberrant inflammatory response is associated with ARDS and multi-organ involvement. ^{Reference Zhang, Zhou and Qiu25}

Serum ferritin, D-dimer, c-reactive protein (CRP), erythrocyte segmentation rate (ESR), procalcitonin, lactate dehydrogenase (LDH), interleukin-2 receptor (IL-2), interleukin-6 (IL-6), and interleukin-10 (IL-10) were found to be elevated and platelet levels were reduced in non-survivors in a cohort of COVID-19 cases in Wuhan, China suggesting the role of hyper-inflammation. ^{Reference Huang, Wang and Li24,Reference Chen, Wu and Chen41–Reference Du, Liang and Yang44} Elevated granulocyte-colony stimulating factor (G-CSF levels) was observed and were notably higher among patients requiring ICU admission. ^{Reference Huang, Wang and Li24} Neutrophilia was reported in COVID-19 non-survivors and may be associated with cytokine storm syndrome induced by viral evasion. ^{Reference Wang, Hu and Hu42} Higher mortality rates may be due to SARS-CoV-2-induced hyper-inflammation observed in a cytokine storm. Using immune-inflammatory laboratory trends such as increased ferritin, D-dimer, IL-6, and CRP may help identify patients who require immunosuppressive treatments such as steroids and selective cytokine blockade along with supportive treatment may reduce mortality rates. The severity of the disease is observed to increase with age and comorbidities such as obesity, cardiovascular disease, and pulmonary disease increase the mortality rates in COVID-19. ^{Reference Pirofski and Casadevall45} The mechanisms of dysfunctional immune pathogenesis are described in Fig. 2(a–f).

Fig. 2.

Pathological immune response in SARS-CoV-2. (a) SARS-CoV-2 enters the lungs due to a high affinity to angiotensin-converting enzyme-2 (ACE-2). (b) Pyroptosis and cytopathic processes along with pattern recognition receptors (PRRs) that identify pathogen-associated molecular patterns (PAMPs) of viral RNA invoke the release of pro-inflammatory cytokines including IL-2, IL-6, IL-7, IL-10, granulocyte colony-stimulating factor (GCSF), interferon-gamma (IFN-γ), interferon gamma-induced protein 10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1 alpha (MIP-1-α), and tumor necrosis factor-α (TNF-α). (c) As opposed to healthy immune responses whereby host cells recruit innate and adaptive immune responses to suppress infection, pathological immune responses promote a pro-inflammatory loop leading to cytokine storm syndrome (CSS). Monocytes and macrophages are recruited possibly due to direct infection by virus leading to the recruitment of helper and suppressor T cells. T cells, monocytes, and macrophages further attract pro-inflammatory cytokines and cytokines thereby establishing a pathogenic pro-inflammatory loop. (d) Cytokine storm causes a systemic pro-inflammatory state across the host system. (e) Lung architecture is compromised leading to pulmonary edema and microvascular leakage observed in severe acute respiratory syndrome (SARS). Antibody-dependent enhancement (ADE), molecular mimicry, and epitope spreading contribute to the severity of pathological immune responses. (f) Damage to the lung architecture and pro-inflammatory state leads to multi-organ damage. Adapted from. ^{Reference Tay, Poh, Rénia, MacAry and Ng40}

Inflammatory pathogenesis in pediatric populations

Most COVID-19 cases are known to be mild or asymptomatic in children. However, a small number develop a multi-system inflammatory syndrome in children (MIS-C) that present with elevated markers of inflammation. The clinical features are similar to those of Kawaski disease and toxic shock syndrome with features unique to COVID-19. ^{Reference Whittaker, Bamford and Kenny46} MIS-C was not reported in the early phases of the pandemic with pediatrics populations having already developed antibodies suggesting the role of adaptive immunological responses. Preliminary case definitions include fever for at least 1 day with elevated inflammatory markers, involving two or more organs, requiring hospitalization, no other plausible diagnosis and diagnosed by RT-PCR, serology, antigen test, or exposure history in the last 4 weeks before the onset of symptoms for SARS-CoV-2. ⁴⁷ Antibody-dependent enhancement against spike proteins are suspected to cause the underlying inflammatory pathology in SARS-CoV-2. The distribution of MIS-C follows a u-shaped curve with severe symptoms manifesting commonly in children younger than 1 year of age. ^{Reference Götzinger, Santiago-García and Noguera-Julián48} Associations with underlying genetics and ethnicities (e.g. Black) have been reported. ^{Reference Jiang, Tang and Levin22}

Gaps in literature

There is a need to advance research in addressing health inequity as certain groups are more vulnerable. ^{Reference Xafis, Schaefer, Labude, Zhu and Hsu49} Certain subpopulations have had a disproportionately higher rate of incidence and mortality of COVID-19 infection. ^{Reference Xafis, Schaefer, Labude, Zhu and Hsu49} The DOHaD concept identifies a causal association between epigenetic changes and disease susceptibility later in life with the disease risk having also been observed to transmit across generations. ^{Reference Heindel and Vandenberg50} Less than 1% of the clinical trials have been conducted in low-income countries. It may be possible that the vaccine efficacy is compromised when being administered to these populations due to their varied underlying response to COVID-19 vaccinations. There is renewed urgency to identify the underlying immunological mechanisms across various subpopulations at a global level, including low- and middle-income countries, as the vaccines are being rolled out.

Implications for vaccine

During the initial phase of the COVID-19 pandemic, neutralizing antibodies after infection were closely monitored with reports suggesting gradual waning until 3 months after SARS-CoV-2 infection. ^{Reference Seow, Graham and Merrick51} T cells responses were also shown to be important as part of protective immunity among patients with COVID-19 infection. ^{Reference Le Bert, Tan and Kunasegaran52} T cell-mediated immune responses may provide sustained immunity even after B cell-mediated immune responses wane. As the world is racing to develop various vaccine strategies and platforms, a new pandemic vaccine development paradigm has been set up that has reduced the development timeframe from 10–15 years to 1–2 years. However, there is a lack of clarity as to how to categorize successful vaccine efficacy testing. ^{Reference Jeyanathan, Afkhami, Smaill, Miller, Lichty and Xing53} With the accelerated development process, there is overlap in preclinical, clinical, and manufacturing of the vaccines. Vaccine candidates have been hailed as safe and effective, thereby resulting in global deployment. As of March 17, 2020, 7 vaccines are available for public use in over 128 countries. The Center for Disease Control and Prevention (CDC) approves and recommends three vaccines including Pfizer-BioNTech, Moderna, and Johnson & Johnson. ⁵⁴ All the approved vaccines are administered via intramuscular injection of the upper arm. Pfizer-BioNtech and Moderna both require two doses 3 weeks and 1 month apart, respectively; Johnson & Johnson only requires one dose. To achieve herd immunity, equitable and robust global access is essential. The ongoing vaccination of high-risk populations is an evolving process such that there may be waning immunity. Given the challenges in the implementation of vaccination programs, it is pertinent that different vaccination platforms and strategies be employed.