Passive Immunisation and Immunoglobulins

Active vaccination trains a person to make their own protective response, which takes one to two weeks and then lasts. Passive immunisation does the opposite: it transfers ready-made antibody, so protection begins within hours but fades over weeks to a few months and leaves no memory.

This makes passive immunisation the tool for situations where active vaccination is too slow or impossible: a defined exposure that demands protection now, a high-risk infant facing a seasonal virus, or a person who cannot make antibody at all. The agents are pooled human immunoglobulins and, increasingly, monoclonal antibodies.

Active versus passive immunisation

The two approaches are complementary, and their properties are mirror images. Active immunisation is slow to take effect but durable and self-renewing; passive immunisation is immediate but short-lived, because the transferred antibody is catabolised with a half-life of about three to four weeks and is never replenished by the recipient.

Passive immunotherapy is in fact the older idea. Serum therapy began in 1890, when Behring and Kitasato showed that antibody-rich serum could prevent and treat diphtheria and tetanus, work that earned the first Nobel Prize in Medicine in 1901; the diphtheria antitoxin that followed cut hospital mortality decades before any vaccine existed.

For some exposures the two are combined, exploiting the strength of each. In rabies and hepatitis B post-exposure care, immunoglobulin gives instant cover while the simultaneously administered vaccine generates the person’s own lasting response, the antibody bridging the gap until active immunity matures.

A practical consequence runs the other way: passively given antibody can neutralise a live vaccine virus, so live vaccines such as measles, mumps and rubella (MMR) or varicella must be deferred for several months after an immunoglobulin product, and immunoglobulin withheld for a couple of weeks after a live vaccine.

Natural passive immunity

The original form of passive immunity is natural. Maternal IgG crosses the placenta in the last trimester, so a newborn begins life with antibody titres mirroring the mother’s, and breast milk adds secretory IgA at the gut surface. This protection wanes over the first six months of life, which sets the timing of infant vaccination and leaves a window of vulnerability; the window is starkest in severe combined immunodeficiency, often unmasked at around six months of age precisely as maternal antibody disappears.

The same biology is the rationale for maternal immunisation: vaccinating in pregnancy raises maternal antibody that crosses to the fetus and protects the newborn against influenza, pertussis and respiratory syncytial virus through the first vulnerable months. Maternal antibody is double-edged, because it also dampens the infant’s response to live vaccines such as measles and rotavirus, one reason those are timed to when it has waned.

Polyclonal immunoglobulins

Polyclonal immunoglobulin is purified from the pooled plasma of thousands of donors, so it contains a broad mixture of antibodies reflecting the donors’ collective immune experience. Manufacture includes deliberate steps to remove and inactivate blood-borne pathogens (solvent-detergent treatment, pasteurisation, low-pH incubation and nanofiltration), which is why modern products have an excellent safety record; the historical transmission of hepatitis through contaminated antibody preparations is what drove these safeguards.

Two kinds are distinguished by how they are sourced. Normal human immunoglobulin (NHIG) is pooled from unselected donors and carries whatever antibodies are common in the population, used where general antibody is needed (measles and hepatitis A post-exposure prophylaxis, and replacement therapy). Specific (hyperimmune) immunoglobulins are prepared from donors with high titres against one agent, giving a concentrated, targeted product: hepatitis B immunoglobulin (HBIG), varicella-zoster immunoglobulin (VZIG), rabies immunoglobulin (RIG), cytomegalovirus (CMV) immunoglobulin and others. Products are given intramuscularly or, for replacement and some high-dose uses, intravenously.

Monoclonal antibodies

A monoclonal antibody is a single, defined antibody produced to a chosen target, rather than a polyclonal mixture. Because every molecule binds the same site, a monoclonal is far more potent by weight than pooled immunoglobulin: a fraction of a milligram of a specific monoclonal can match a hundred milligrams or more of polyclonal product.

Made by recombinant technology, they are pure, consistent and scalable. Engineering the antibody’s Fc region to bind the recycling receptor FcRn can extend its half-life from a few weeks to around three months, so a single dose protects for a whole season. Their limitation is cost and, for a rapidly changing virus, the risk that the target epitope mutates and escapes.

Against viral disease the leading examples protect the respiratory tract. Palivizumab, the first monoclonal antibody licensed for an infectious disease, targets the respiratory syncytial virus (RSV) fusion protein and is given monthly through the season to high-risk infants. It has now been largely superseded by nirsevimab, a long-acting antibody that protects for an entire RSV season with a single dose and reduces medically attended RSV disease by around 75%. Other monoclonals against viral disease include:

• COVID-19: the combination used for pre-exposure prophylaxis in immunocompromised people, its usefulness varying as the virus evolves.
• Ebola virus disease: the antibody combinations that became the first approved treatments.
• HIV: ibalizumab for multidrug-resistant infection.

Not every therapeutic monoclonal acts on the virus. Rituximab, an anti-CD20 antibody, treats EBV-driven post-transplant lymphoproliferative disorder (PTLD) by depleting the proliferating B cells rather than the virus itself, a reminder that antibody therapy in virology includes host-directed as well as antiviral agents.

When to use passive immunisation

Passive immunisation is indicated in three broad situations: immediately after a defined exposure in a non-immune person, as seasonal prophylaxis for those at high risk, and as protection for people who cannot mount their own response. Timing is decisive, because antibody only helps if it is present before or very early in the infection.

Product	Type	Main indication	Timing
Hepatitis B immunoglobulin (HBIG)	Polyclonal, specific	Neonate of an HBsAg-positive mother; non-immune percutaneous or sexual exposure	With vaccine, as soon as possible (neonate within 12 hours)
Rabies immunoglobulin (RIG)	Polyclonal, specific	Category III rabies exposure in a non-immune person	With the first vaccine dose, infiltrated into the wound
Varicella-zoster immunoglobulin (VZIG)	Polyclonal, specific	Exposed susceptible at high risk (immunocompromised, neonate, pregnant)	As soon as possible after exposure
Normal human immunoglobulin (NHIG)	Polyclonal, broad	Measles or hepatitis A post-exposure in those who cannot be vaccinated	Measles: within 6 days of exposure
Palivizumab or nirsevimab	Monoclonal	RSV prophylaxis in high-risk (palivizumab) or all (nirsevimab) infants	Before or at the start of the RSV season

The rabies example shows why timing matters most: rabies immunoglobulin is infiltrated into and around the wound at the same visit as the first vaccine dose, and gives no added benefit once the vaccine has begun to generate the person’s own antibody (after about the first week). For hepatitis B, the neonate of an infected mother receives immunoglobulin and vaccine at birth, which together prevent the great majority of perinatal infections.

How long protection lasts

Passive protection is inherently temporary, and its duration follows the half-life of the transferred antibody. Ordinary IgG has a half-life of about three weeks, so a polyclonal immunoglobulin protects for weeks to a few months; the Fc-engineered monoclonals stretch this to around three months. The other determinant is timing relative to infection: antibody works best given before exposure, keeps useful benefit if given early after exposure but before symptoms, and does little once disease is established, because by then the virus has spread beyond the reach of circulating antibody.

The principle is visible across several agents. For respiratory syncytial virus, prophylactic antibody must cover the whole season, achieved by monthly palivizumab or a single long-acting dose of nirsevimab, and gives no benefit once infection has taken hold. Cytomegalovirus immunoglobulin in transplant recipients is given through the high-risk first months after transplantation, its effect lasting only while the antibody persists. For Lassa fever, immune plasma can be life-saving but only within the first few days of illness, survival falling sharply once treatment is delayed beyond that window. In each case the benefit depends on the antibody being in place before the infection outruns it.

Immunoglobulin replacement in immunodeficiency

A distinct use of antibody is not prophylaxis against one virus but replacement of antibody that the patient cannot make. In primary antibody deficiencies such as X-linked agammaglobulinaemia and common variable immunodeficiency, regular immunoglobulin replacement (intravenous or subcutaneous, every few weeks) supplies a broad antibody repertoire and prevents recurrent infection. The same principle supports some patients with secondary antibody deficiency from malignancy or its treatment. This is lifelong therapy, dosed to maintain a protective trough level, and is the reason immunoglobulin is a scarce, demand-sensitive resource.

Practical aspects

Several practical points govern safe use. Antibody is given by the intramuscular, subcutaneous or intravenous route and acts at once; its useful protection lasts weeks to a few months. Storage requires a cold chain (2 to 8 degrees Celsius), and products must not be frozen.

Adverse effects are usually mild infusion-related reactions. Beyond these, several safety points warrant emphasis:

• Selective IgA deficiency: these patients can have anaphylaxis to immunoglobulin products through anti-IgA antibodies, so a history is important.
• Serum sickness: antibody raised in animals, as a few antitoxins still are, can provoke it, which is why human-derived products are preferred where available.
• Informed consent: because these are pooled human blood products, consent should cover that origin and the residual, very low theoretical infection risk despite modern pathogen-inactivation steps.
• Live vaccine interaction: timing must be planned around when both an immunoglobulin and a live vaccine are due.

South African context

Passive immunisation in South Africa centres on a small number of products used within national guidelines. Hepatitis B immunoglobulin is given with the vaccine to neonates of HBsAg-positive mothers, alongside the targeted birth dose, to prevent perinatal transmission. Rabies immunoglobulin is a core part of category III post-exposure prophylaxis, infiltrated into the wound with the first vaccine dose, and its supply and correct use are a recurring practical concern given the burden of dog-bite exposures.

For measles, normal human immunoglobulin is used for post-exposure protection of exposed contacts who cannot receive the vaccine (infants, pregnant women, and the immunocompromised), given within six days of exposure per NICD guidance. Varicella-zoster immunoglobulin is reserved for high-risk susceptible contacts, including HIV-infected and other immunocompromised patients.

Immunoglobulin	Type	Indication in South Africa	Timing
Hepatitis A (NHIG)	Polyclonal, broad	Post-exposure protection of contacts who cannot be vaccinated	Within 2 weeks of exposure
Varicella-zoster (VZIG)	Polyclonal, specific	Exposed susceptible at high risk (immunocompromised, neonate, pregnant)	As soon as possible, within ~10 days
Hepatitis B (HBIG)	Polyclonal, specific	Neonate of an HBsAg-positive mother; non-immune percutaneous or sexual exposure	With vaccine; neonate within 12 hours
Rabies (RIG)	Polyclonal, specific	Category III exposure in a non-immune person	With the first vaccine dose, infiltrated into the wound
Measles (NHIG)	Polyclonal, broad	Post-exposure for contacts who cannot be vaccinated (infants, pregnant, immunocompromised)	Within 6 days of exposure

Access shapes practice. Monoclonal RSV prophylaxis (palivizumab, and the longer-acting nirsevimab) is not part of the public-sector programme and is largely confined to private care, so most South African infants are not covered against RSV. Intravenous immunoglobulin for primary immunodeficiency is available but is a costly, supply-limited resource managed through specialist services. Adverse events to these blood products are reported to the South African Health Products Regulatory Authority.